Model‐informed precision dosing of vancomycin for rapid achievement of target area under the concentration‐time curve: A simulation study

Abstract In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration‐time curve (AUC) of vancomycin on the first and second day (AUC0–24, AUC24–48, respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model‐informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8–1.2. The Bayesian posterior probability of achieving the AUC24–48 range increased from 51.3% (a priori probability) to 77.5% after using two‐point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0–24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady‐state (AUCSS) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second‐day trough and peak sampling provided accurate AUC24–48, and first‐day sampling may assist in rapidly achieving therapeutic AUC24–48, although the AUCSS should be re‐estimated in patients with reduced kidney function owing to its unreliable predictive performance

Factors Affecting Treatment and Recurrence of Clostridium difficile Infections

The antimicrobial agents vancomycin and metronidazole have been used to treat Clostridium difficile infections (CDIs). However, it remains unclear why patients are at risk of treatment failure and recurrence. Therefore, this study retrospectively examined 98 patients with CDIs who were diagnosed based on the detection of toxin-positive C. difficile to determine the risk factors affecting drug treatment responses and the recurrence of CDI. No significant difference was observed in the cure rate or dosage between the vancomycin and metronidazole groups. The 90-d mortality rate and total number of drugs associated with CDIs, including antiinfective agents used within 2 months before the detection of toxin-positive C. difficile, were significantly lower in the treatment success group than in the failure group. The total number of antiinfective agents and gastric acid-suppressive agents used during CDI therapy was also significantly lower in the success group than in the failure group. The period from the completion of CDI therapy to restarting the administration of anticancer agents and steroids was significantly longer in patients without than in patients with recurrence. These results indicate that the total number of drugs associated with CDIs should be minimized to reduce the risk of CDIs, that not only antibiotics but also gastric acid-suppressive agents should be discontinued during CDI therapy to increase therapeutic efficacy, and that the use of anticancer agents and steroids should be delayed as long as possible after patients are cured by CDI therapy to prevent recurrence

Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in a murine thigh infection model

Objectives: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. Methods: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. Results: Target values offCmax/MIC (r2 = 0.94) of teicoplanin for static effect and 1 log10 kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MSSA were 30.4 and 70.56, respectively. Target values of fCmax/MIC (r2 = 0.91) of teicoplanin for static effect and 1 log10 kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MRSA were 54.8 and 76.4, respectively. Conclusion: These results suggest thatfCmax/MIC and fAUC24/MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA

Characterization of chimpanzee iPSCs.

<p>(<b>a</b>) Differentiation into three germ layers in vitro. The chimpanzee iPSC lines can generate SOX17⁺ (endoderm), BRACHYURY⁺ (mesoderm), and βIII-tubulin⁺ (ectoderm) cells. Scale bars, 100 µm. (<b>b</b>) Tissue morphology of a representative teratoma derived from the chimpanzee iPSC lines generated with TS12KOS vector. G, glandular structure (endoderm); C, cartilage (mesoderm); CE, Cuboidal Epithelium structure (ectoderm); MP, melanin pigment (ectoderm). Scale bars, 100 µm. (<b>c</b>) Principal Component Analysis. All data sets were classified into three principal components, PC1 (47.62%), PC2 (29.81%), and PC3 (22.56%), and then simplified into three-dimensional scores. Percentage shows the portion of variance in each component. The position of chimpanzee iPSC lines is closely placed to that of human ESCs and iPSCs. (<b>d</b>) Hierarchical clustering of chimpanzee iPSCs, human iPSCs and ESCs. The data sets of all genes investigated were clustered according to Euclidean distance metrics. The data sets of chimpanzee iPSCs, human ESC and iPSC lines, and various human tissues were classified into separate branches. The datasets of human ESCs and various tissues referred for Gene Expression Omnibus datasets, GSE22167 and GSE33846, respectively.</p

Generation of a new temperature-sensitive Sendai virus vector, TS12KOS.

<p>(<b>a</b>) Comparison of schematic structures among the newly constructed Sendai virus (SeV) vector, TS12KOS, and previous vectors. The TS12KOS vector contains three point mutations in the RNA polymerase–related gene (P) and carries the coding sequences of <i>KLF4</i> (K), <i>OCT3/4</i> (O), and <i>SOX2</i> (S) in the KOS direction. In comparison, the HNL/TS15 c-Myc vector carries two additional mutations, L1361C and L1558I, in the large polymerase (L) gene and an exogenous c-<i>MYC</i> cDNA sequence inserted between the hemagglutinin-neuraminidase (HN) and L genes, and the conventional vectors individually carry three reprogramming factors as indicated. (<b>b</b>) iPS cell generation from human skin-derived fibroblasts. The efficiency of iPS cell generation was significantly higher using the TS12KOS vector than with the conventional vectors at all multiplicities of infection (MOI) tested. iPSC colonies were identified on day 28 of induction by the appearance of alkaline phosphatase-positive (AP⁺) colonies with embryonic stem (ES) cell-like colony morphology. N1, N2, and N3 represent individual healthy volunteers. Experiments were conducted in triplicate (mean ± SD). *<i>P</i><0.01, TS12KOS vector versus conventional vectors, Student's t-test. (<b>c</b>) Temperature shift from 37°C to 36°C for the indicated periods in iPSC generation. Data are means ± SD of three independent experiments. ^#<i>P</i><0.05, Experiment 2, 3 and 4 versus Experiment 1. Student's t-test. (<b>d</b>) Nested RT-PCR analysis of SeV vector elimination after the temperature shift from 37°C to 38°C in human fibroblast-derived iPSCs. The elimination of TS12KOS vector was faster than the conventional vectors.</p

Generation of chimpanzee iPSCs with the TS12KOS vector.

<p>(<b>a</b>) Summary of chimpanzee iPSC generation. iPSCs were generated from the blood cells of two chimpanzee individuals with TS12KOS or the conventional SeV vectors. (<b>b</b>) Effect of the T lymphocyte stimulation on iPSC generation. Experiments were conducted in triplicate (mean ± SD). *<i>P</i><0.01, PHA versus anti-CD3 antibody or Con A stimulations, Student's t-test. (<b>c</b>) Colony morphology and AP staining of iPSCs from stimulated T lymphocytes. (<b>d</b>) Phase contrast images, immunofluorescence for pluripotency markers, and alkaline phosphatase (AP) staining of chimpanzee iPSC lines. C101, C201, C205, and C402 are described in <b>Fig. 3a</b>. Scale bars, 200 µm. (<b>e</b>) RT-PCR analysis of SeV and human ES cell markers. SeV, first RT-PCR for SeV; nested, nested RT-PCR for SeV; 201B7, control human iPSC line; SeV(+), Day 7 SeV-infected human fibroblasts. (<b>f</b>) PCR products with primers that can distinguish chimpanzee and human genomes. Chimpanzee PCR products; 782, 472 and 504 bps, Human PCR products; 203, 245, 278 bps. (<b>g</b>) Chromosomal analyses of chimpanzee iPSC lines generated with the TS12KOS vector. (<b>h</b>) TCR gene recombination. Genes from the chimpanzee iPSC lines were digested with the indicated enzymes and hybridized with the TCR probes by Southern blotting. Arrows indicate the germ bands of TCR genes. HeLa and 201B7: human cell lines, MT4: human T cell line, HSP-239: chimpanzee T cell line.</p

Characterization of human iPSCs generated by the TS12KOS vector.

<p>(<b>a</b>) iPSC generation from human peripheral blood cells. Experiments were conducted in triplicate (mean ± SD). N1, N2, and N3 indicate individual healthy volunteers. *<i>P</i><0.01, TS12KOS vector versus conventional vectors, Student's t-test. (<b>b</b>) Nested RT-PCR analysis of the elimination of SeV vectors after the temperature shift from 37°C to 38°C. (<b>c</b>) Phase contrast images, immunofluorescence for pluripotency markers, and alkaline phosphatase (AP) staining of iPSC lines. The iPSC lines N2-1 and BN2-1 and BN2-2 were derived from the skin-derived fibroblasts and blood cells of N2 healthy volunteer, respectively. Scale bars, 200 µm. (<b>d</b>) RT-PCR analysis of Sendai virus and human ES cell markers. SeV, first RT-PCR for SeV; nested, nested RT-PCR for SeV; 201B7, control human iPSC line; SeV(+), Day 7 SeV-infected human fibroblasts. (<b>e</b>) Chromosomal analyses of iPSC lines generated with the TS12KOS vector. (<b>f</b>) Tissue morphology of a representative teratoma derived from iPSC lines generated with the TS12KOS vector. G, glandular structure (endoderm); C, cartilage (mesoderm); MP, melanin pigment (ectoderm). Scale bars, 100 µm.</p

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