Background: Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT .MIC ) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.Objectives: To characterize meropenem pharmacokinetics in variable CL CR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.Methods: A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CL CRRT or CL no-CRRT ). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT .MIC in 90% of patients.Results: A total of 101 patients were studied: median 63 years (range 49-70), 56% male, . 32% had a CL CR .60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC 90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CL no-CRRT was 59% lower in impaired (CL CR 30 mL/min) compared to normal (CL CR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC 90 in patients with CL CR ,60 mL/min. Patients with CL CR of 60 to ,90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CL CR !90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.Conclusions: Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.
Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.
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