iAlthough ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (<34 or >34 weeks) and postnatal age (PNA) (<7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of <34 weeks and PNA of <7 days, 75 mg/kg every 12 h for GA of <34 weeks and PNA of >8 and <28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of <28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.
f Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of <30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (<32 mg/liter) for 75% of the dosing interval. P iperacillin-tazobactam is approved by the U.S. Food and Drug Administration for the treatment of adults and children of Ͼ2 months of age with infections due to susceptible bacteria; however, the drug is not approved for use in younger infants, including those born prematurely. In spite of this, piperacillin-tazobactam is extensively used "off-label" in young infants for treatment of systemic infections, including bacteremia and complicated intra-abdominal infections, such as necrotizing enterocolitis (1). Because these infections in premature infants are associated with devastating outcomes, such as death and neurodevelopmental impairment (2, 3), appropriate dosing recommendations for agents such as piperacillin-tazobactam are needed. Recommended piperacillin-tazobactam dosing for young infants in sources like Neofax (4) and The Harriet Lane Handbook (5) rely on combinations of birth weight, gestational age, postmenstrual age (PMA), and postnatal age (PNA), which are cumbersome to implement clinically and more importantly are supported by very small and limited clinical trials in this population.The pharmacokinetics (PK) of piperacillin-tazobactam has not been well characterized for premature infants. The drug is primarily renally eliminated by glomerular fi...
Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.
Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.
Fluconazole prophylaxis decreased Candida albicans and 'non-albicans' Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.