Necrotizing fasciitis (NF) is a rapidly progressing infection of the soft tissues associated with high morbidity and mortality and hence it is a surgical emergency. Early diagnosis and treatment are of paramount importance. LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) and SIARI (Site other than lower limb, Immunosuppression, Age, Renal impairment, and Inflammatory markers) scoring systems have been established for early and accurate diagnosis of necrotizing fasciitis. This study compared the two scoring systems for diagnosing NF, predicting management, and elucidating the prognostic performance for re-operation and mortality.Necrotizing fasciitis (NF) is a rapidly progressing bacterial infection of the soft tissues associated with a high mortality rate of approximately 50%. It is characterized by inflammation and necrosis arising from the fascia involving muscles and subcutaneous fat with resulting necrosis of the overlying skin, which spreads along the subcutaneous plane with the speed of spread being directly proportional to the thickness of the subcutaneous layer.Ertapenem is a widely used antibiotic; however, its pharmacokinetics has not been fully evaluated in children with renal impairment. A physiologically based pharmacokinetic (PBPK) model of ertapenem was established and validated to simulate its disposition in the healthy population and adults with renal impairment, as well as to predict the exposure in pediatric patients with renal impairment. The simulated PBPK modeling results and the observed data of ertapenem after intravenous administration of various regimens were consistent according to the fold error values of less than . Furthermore, %T > MIC of ertapenem was evaluated using the PBPK model. The Cmax was not significantly changed in pediatric patients with renal impairment compared to healthy children. However, the AUC was 1.42-fold, 1.84-fold, 2.37-fold, and 3.52-fold higher in mild, moderate, severe renal impairment, and end-stage renal disease, respectively, than that in healthy children and the doses of ertapenem were reduced to 13 mg/kg b.i.d, 9 mg/kg b.i.d, 6 mg/kg b.i.d, and 5 mg/kg b.i.d, respectively. The probability of achieving 40%T > MIC (MIC ≤ 4 μg/mL) was nearly 100% throughout the recommended dosing interval. In conclusion, our model can be used as a tool to generate better predictions for the most effective ertapenem dosing in pediatric patients.Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime.

The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment.

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Mishita
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Journal of Clinical & Experimental Nephrology