Dose Individualization of Cefepime for Febrile Neutropenia in Patients With Lymphoma or Multiple Myeloma: Implications for Therapeutic Drug Monitoring.

BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.

Reduced nephrotoxicity with vancomycin therapeutic drug monitoring guided by area under the concentration-time curve against a trough 15-20 µg/mL concentration.

Vancomycin is often employed as an antibacterial agent against Gram-positive bacteria, although dose-dependent nephrotoxicity is a concern. Although the risk may be reduced by therapeutic drug monitoring (TDM) guided by area under the concentration-time curve (an attempt to target an AUC > 400 µg•h/mL by Bayesian prediction: AUC400-guided TDM), the clinical efficacy of AUC400-guided TDM compared with trough concentration-guided TDM within 15-20 µg/mL (Trough15-20-guided TDM) has yet to be determined. We aimed to retrospectively evaluate the difference in the incidence rate of acute kidney injury (AKI), classified according to the Acute Kidney Injury Network, between these TDM groups. Individual AUC in the AUC400-guided TDM group was calculated by Bayesian prediction using trough and peak concentrations (within 3 h after the end of infusion). The AKI incidence in the Trough15-20-guided TDM group was 28.8% (15/52 patients) compared with an AKI incidence in the AUC400-guided TDM group of 9.1% (2/22 patients). Application of AUC400-guided TDM was identified as an independent factor for avoiding the incidence of AKI by Cox hazard regression analysis [hazard ratio = 0.168, 95% confidence interval (CI) 0.034-0.839] and logistic regression analysis (odds ratio = 0.037, 95% CI 0.003-0.285). As the estimated glomerular filtration rate (eGFR) improved, the surrogate target trough concentration for an AUC > 400 µg•h/mL was lowered (intercept 15.0074, slope -0.0598). In conclusion, AUC400-guided TDM may be superior to Trough15-20-guided TDM for the reduction of nephrotoxicity during vancomycin therapy.

Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells.

DNA methylation plays critical roles in the development and differentiation of mammalian cells, and its dysregulation has been implicated in oncogenesis. This study was designed to determine whether DNA hypomethylation-associated aberrant gene expression is involved in adult T-cell leukemia (ATL) leukemogenesis. We isolated hypomethylated DNA regions of ATL cells compared with peripheral blood mononuclear cells from a carrier by a methylated CpG-island amplification/representational difference analysis method. The DNA regions identified contained MEL1, CACNA1H, and Nogo receptor genes. Sequencing using sodium bisulfite-treated genomic DNAs revealed the decreased methylated CpG sites, confirming that this method detected hypomethylated DNA regions. Moreover, these hypomethylated genes were aberrantly transcribed. Among them, MEL1S, an alternatively spliced form of MEL1 lacking the PR (positive regulatory domain I binding factor 1 and retinoblastoma-interacting zinc finger protein) domain, was frequently transcribed in ATL cells, and the transcriptional initiation sites were identified upstream from exons 4 and 6. Transfection of MEL1S into CTLL-2 cells conferred resistance against transforming growth factor beta (TGF-beta), suggesting that aberrant expression of MEL1S was associated with dysregulation of TGF-beta-mediated signaling. Although Tax renders cells resistant to TGF-beta, Tax could not be produced in most fresh ATL cells, in which MEL1S might be responsible for TGF-beta resistance. Our results suggest that aberrant gene expression associated with DNA hypomethylation is implicated in leukemogenesis of ATL.