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A vancomycin steady‐state trough concentration (Cmin) of 15‐20 mg/L is recommended for achieving a ratio of the 24‐hour area under the curve to the minimum inhibitory concentration (AUC0‐24/MIC) of ≥400 in adults. Since few paediatric data are available, our objectives were to (a) measure the pharmacokinetic indices of vancomycin and (b) determine the correlation between Cmin and AUC0‐24/MIC in paediatric patients. Population‐based pharmacokinetic modelling was performed for paediatric patients to estimate the individual parameters. The relationship between Cmin and the calculated AUC0‐24/MIC was explored using linear regression and a probabilistic framework. A sensitivity analysis was also conducted using Monte Carlo simulations. Body‐weight significantly influenced the pharmacokinetics of vancomycin. Based on real data and simulations, Cmin ranges of 5.0‐5.9 and 9.0‐12.9 mg/L were associated with AUC0‐24/MIC ≥400 for MIC values of ≤0.5 and ≤1 mg/L, respectively. Vancomycin regimens of 10 and 15 mg/kg every 6 hours achieved a Cmin of 5.0‐5.9 mg/L and AUC0‐24/MIC ≥400 in >90% of the children when MIC was ≤0.5 mg/L. At a MIC of ≤1 mg/L, vancomycin at 15 mg/kg every 6 hours achieved Cmin of 9.0‐12.9 mg/L and AUC0‐24/MIC ≥400 in 2.0‐ and 1.6‐fold as many children compared to a dose of 10 mg/kg every 6 hours, respectively. Vancomycin Cmin values of 5.0‐12.9 mg/L were strongly predictive of achieving AUC0‐24/MIC ≥400, and rational dosing regimens of 10‐15 mg/kg q6h were required in paediatric patients, depending on the pathogen. [ABSTRACT FROM AUTHOR]

Background Patients colonized with carbapenem-susceptible Pseudomonas aeruginosa (CSPA) strains upon admission to the intensive care unit (ICU) tend to be quickly followed by detected carbapenem-resistant P. aeruginosa strains after admission. Objective To assess the risk factors associated with the quick loss of carbapenem susceptibility and to identify time threshold of prior antimicrobial exposure for the loss during ICU stay. Setting A tertiary-care teaching hospital with 2560 beds located in the northwest region of China. Method A retrospective observational study was conducted between January 2013 and April 2016 at ICUs. Logistic regression analysis was used to assess risk factors, and receiver operating characteristic (ROC) analyses were constructed to identify the time threshold. Main outcome measure The time threshold and risk factors for the quick loss of carbapenem susceptibility. Results Among the 84 patients with CSPA initially, 32 (38.1%) patients were observed to have a loss of carbapenem susceptibility during ICU stay. Logistic regression analyses showed that previous carbapenem exposure was only independently associated with the loss of carbapenem susceptibility (odds ratio 13.16; 95% CI 3.13-55.24; p < 0.001). The optimal cut-off was 3.5 days on ROC curve, indicating the high risk for loss of susceptibility. Conclusion In order to alleviate selective pressure caused by antipseudomonal carbapenems exposure, continued research is needed to determine the most appropriate carbapenems treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: The substantial variability in the antiplatelet efficacy of clopidogrel has raised major concerns. Molecular epidemiological research suggests that ABCB1 C3435T polymorphism may be associated with clopidogrel response, but results remain controversial. To derive a more precise evaluation of the associations between ABCB1 C3435T polymorphism and the clinical efficacy of clopidogrel, we have conducted a PRISMA-compliant meta-analysis. Methods: The PubMed and EMBASE databases were searched for eligible studies up to 25 October 2016. The odds ratio (OR), the standard mean difference (SMD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. Results: Overall, 28 related studies involving 23,243 patients were analyzed. No association was found between the ABCB1 polymorphisms and the primary outcome. In the subgroup analysis, the C3435T mutation significantly reduced platelet activity as tested by the LTA assay in the dominant (SMD −0.140, 95% CI −0.272 to −0.009, P = 0.036) and heterozygous (SMD −0.154, 95% CI −0.290 to −0.017, P = 0.027) models, but the result lacked robustness in the sensitivity analysis. A significant association between the C3435T polymorphism and bleeding risk was also observed with low heterogeneity in the dominant (OR 1.805, 95% CI1.124-2.900, P =0.015, I = 0%), homozygous (OR 1.952, 95% CI 1.055-3.611, P = 0.033, I = 13.2%) and heterozygous (OR 1.793, 95% CI 1.091-2.946, P = 0.021, I = 0%) models in Asian patients. Conclusions: The results of the meta-analysis suggest that ABCB1 C3435T polymorphism may increase the risk of bleeding in Asian patients treated with clopidogrel. The implied relationship needs to be verified in future basic genetic pharmacology studies. [ABSTRACT FROM AUTHOR]

Invasive fungal disease ( IFD) is a significant cause of morbidity and mortality in hospitalized patients. To maximize the efficacy of voriconazole treatment, the study established the relationship between voriconazole pharmacokinetic/pharmacodynamic ( PK/ PD) and probability of response and optimized voriconazole dosage regimen in patients with IFD based on Monte Carlo simulation. Forty-four patients proven with IFD were involved in this study. Among them, the overall cure rate was 75% (33/44) and there was a significant difference between Cmin/ MIC values in patients with lack of response ( n = 11) and those with successful response ( n = 33) (mean value: 1.91 vs. 11.33; P < 0.05). Logistic regression model showed a high correlation between voriconazole Cmin/ MIC ratio and clinical response ( P = 0.044, OR = 1.349). According to Monte Carlo simulation results under different voriconazole dosing regimens, we could draw a conclusion that 200 mg voriconazole administered intravenously or orally twice daily for Candida infections and 300 mg administered orally or with 200 mg administered intravenously twice daily for Aspergillus infections were rational, which could achieve a value of the cumulative fraction of response >90%. This study built the relationship between voriconazole PK/ PD and clinical response and obtained the reasonable empirical dosage regimen, which can be used to customize individual dosage regimen and improve the efficacy of voriconazole treatment. [ABSTRACT FROM AUTHOR]

Study Objectives To assess the pharmacokinetic and pharmacodynamic ( PK/ PD) properties of voriconazole and to investigate the relationship between PK/ PD parameters and the efficacy of a fixed-dose oral regimen in the treatment of invasive fungal infections ( IFIs). Design Prospective and observational PK/ PD study. Setting A university-affiliated medical center. Patients Fifteen hospitalized patients with proven IFIs who were treated with oral voriconazole for at least 2 weeks. Methods We investigated the PK/ PD properties of voriconazole using a noncompartmental analysis in 15 patients. Results Marked interpatient variation in voriconazole pharmacokinetic properties was noted including peak plasma concentrations (median 2.31 mg/L, range 1.06-4.01 mg/L), 12-hour area under the plasma concentration-time curve ( AUCτ) (median 21.18 hr mg/L, range 7.71-42.07 hr mg/L), ratio of the unbound drug AUC over 24 hours ( fAUC24) divided by the minimum inhibitory concentration ( fAUC24: MIC; median 62.61, range 6.48-415.30), and the free trough plasma concentration (Cmin) divided by the MIC ( fCmin: MIC; median 1.81, range 0.46-15.52). There was a good correlation between voriconazole Cmin and AUCτ ( R2 = 0.805). Voriconazole therapy was effective in 66.7% of patients (10/15). No significant difference was observed with regard to successful clinical response between the patients with a fAUC24: MIC and fCmin: MIC values higher than 25 and higher than 1 (10/12 vs 10/13, respectively; χ2 = 1.61, p=0.688). Conclusion There is substantial interpatient variability in the PK/ PD properties of voriconazole. fAUC24: MIC values higher than 25 and fCmin: MIC values higher than 1 may predict clinical response in patients with IFIs. Designing an optimal dosage regimen based on individual PK/ PD properties will improve the efficacy in patients with IFIs. [ABSTRACT FROM AUTHOR]

Background: Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients. Voriconazole is commonly used to prevent and treat IPA in the clinic, but the optimal prophylactic antifungal regimen is unknown. The objective of this study was to clarify the mechanism underlying how voriconazole prevents IPA based on a target cellular pharmacokinetics/pharmacodynamics model, with the aim of identifying a way to design an optimal prophylactic antifungal regimen.Methods: A nystatin assay was used to establish a target-cells model for A. fumigatus infection. An inhibitory effect sigmoid Emax model was developed to explore the cellular PK/PD breakpoint, and Monte Carlo simulation was used to design the prophylactic antifungal regimen.Results: The intracellular activity of voriconazole in the target cells varied with its concentration, with the minimum inhibitory concentration (MIC) being an important determinant. For A. fumigatus strains AF293 and AF26, voriconazole decreased the intracellular inoculum by 0.79 and 0.84 lg cfu, respectively. The inhibitory effect sigmoid Emax model showed that 84.01% of the intracellular inoculum was suppressed by voriconazole within 24 h, and that a PK/PD value of 35.53 for the extracellular voriconazole concentration divided by MIC was associated with a 50% suppression of intracellular A. fumigatus. The Monte Carlo simulation results showed that the oral administration of at least 200 mg of voriconazole twice daily was yielded estimated the cumulative fraction of response value of 91.48%. Concentration of voriconazole in the pulmonary epithelial lining fluid and the plasma of > 17.77 and > 1.55 mg/L, respectively, would ensure the PK/PD > 35.53 for voriconazole against most isolates of A. fumigatus and may will be benefit to prevent IPA in clinical applications.Conclusions: This study used a target cellular pharmacokinetics/pharmacodynamics model to reveal a potential mechanism underlying how voriconazole prevents IPA and has provided a method for designing voriconazole prophylactic antifungal regimen in immunosuppressed patients. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration–time curve to minimum inhibitory concentration (AUC 24 /MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC 24 /MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC ≤ 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients. [ABSTRACT FROM AUTHOR]

This study evaluated whether contemporary echinocandin regimens achieved pharmacokinetic/pharmacodynamic targets in ICU patients and general patient populations (GPPs) and assessed caspofungin (CAS) regimens in hepatic impairment (HI) patients. A Monte Carlo simulation was performed using previously published data. Recommended dosing regimens of echinocandins in ICU patients, GPPs and healthy volunteers were evaluated: 70 mg loading dose then 50 mg maintenance dose (70/50 mg) for CAS; 100 mg q24h for micafungin (MCF); and 200/100 mg for anidulafungin (ANF). Moreover, CAS 70 mg and 100 mg q24h in GPPs, and CAS 70/50 mg and 70/35 mg in mild and moderate HI patients, respectively, were evaluated. Cumulative fraction of response (CFR) was calculated for each dosing regimen. For Candida albicans , CFRs for the recommended doses of CAS, MCF and ANF were 95.8%, 13.5% and 50.5% in ICU patients and 96.3%, 42.4% and 61.6% in GPPs, respectively; for Candida glabrata , CFRs were 99.4%, 90.6% and 44.6% in ICU patients and 99.5%, 97.1% and 59.8% in GPPs. For Candida parapsilosis , CFRs of echinocandins for standard regimens were <70%; only CAS 100 mg q24h achieved the target CFR. CAS 70/50 mg and 70/35 mg in mild and moderate HI patients were appropriate. Considerable interindividual variability was observed. For C. albicans and C. glabrata , CAS is good choice both for ICU and other patient populations, but for C. parapsilosis an increased dose should be considered. For MCF and ANF, administering higher doses with longer dosing intervals achieves better target attainment and should be investigated in clinical trials. [ABSTRACT FROM AUTHOR]