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Antimicrobial Agents and Chemotherapy Dec 2019Adults with cystic fibrosis (CF) frequently harbor , which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active... (Clinical Trial)
Clinical Trial
Adults with cystic fibrosis (CF) frequently harbor , which is increasingly antibiotic resistant. Telavancin is a once-daily rapidly bactericidal antibiotic active against methicillin-, linezolid-, and ceftaroline-resistant Because CF patients experience alterations in pharmacokinetics, the optimal dose of telavancin in this population is unknown. Adult CF patients ( = 18) admitted for exacerbations received 3 doses of telavancin 7.5 mg/kg of body weight (first 6 patients) or 10 mg/kg (final 12 patients) every 24 h (q24h). Population pharmacokinetic models with and without covariates were fitted using the nonparametric adaptive grid algorithm in Pmetrics. The final model was used to perform 5,000-patient Monte Carlo simulations for multiple telavancin doses. The best fit was a 2-compartment model describing the volume of distribution of the central compartment ( ) as a multiple of total body weight (TBW) and the volume of distribution of the central compartment scaled to total body weight () normalized by the median observed value ( = × TBW/52.1) and total body clearance (CL) as a linear function of creatinine clearance (CRCL) (CL = CL + CL × CRCL), where CL represents nonrenal clearance and CL represents the slope term on CRCL to estimate renal clearance. The mean population parameters were as follows: , 4.92 ± 0.76 liters · kg; CL, 0.59 ± 0.30 liters · h; CL, 5.97 × 10 ± 1.24 × 10; (volume of the peripheral compartment), 3.77 ± 1.41 liters; (intercompartmental clearance), 4.08 ± 2.17 liters · h The free area under the concentration-time curve (AUC) values for 7.5 and 10 mg/kg were 30 ± 4.6 and 52 ± 12 mg · h/liter, respectively. Doses of 7.5 mg/kg and 10 mg/kg achieved 76.5% and 100% probability of target attainment (PTA) at a AUC/MIC threshold of >215, respectively, for MIC of ≤0.12 mg/liter. The probabilities of reaching the acute kidney injury (AKI) threshold AUC (763 mg · h · liter) for these doses were 0% and 0.96%, respectively. No serious adverse events occurred. Telavancin 10 mg/kg yielded optimal PTA and minimal risk of AKI, suggesting that this FDA-approved dose is appropriate to treat acute pulmonary exacerbations in CF adults. (The clinical trial discussed in this study has been registered at ClinicalTrials.gov under identifier NCT03172793.).
Topics: Adult; Algorithms; Aminoglycosides; Anti-Bacterial Agents; Cystic Fibrosis; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Prospective Studies; Staphylococcal Infections
PubMed: 31685468
DOI: 10.1128/AAC.01914-19 -
Antimicrobial Agents and Chemotherapy Jan 2022Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including... (Clinical Trial)
Clinical Trial
Our study aimed to describe the population pharmacokinetics (PK) of vancomycin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO), including those receiving concomitant renal replacement therapy (RRT). Dosing simulations were used to recommend maximally effective and safe dosing regimens. Serial vancomycin plasma concentrations were measured and analyzed using a population PK approach on . The final model was used to identify dosing regimens that achieved target exposures of area under the curve (AUC) of 400-700 mg · h/liter at steady state. Twenty-two patients were enrolled, of which 11 patients received concomitant RRT. In the non-RRT patients, the median creatinine clearance (CrCL) was 75 ml/min and the mean daily dose of vancomycin was 25.5 mg/kg. Vancomycin was well described in a two-compartment model with CrCL, the presence of RRT, and total body weight found as significant predictors of clearance and central volume of distribution (). The mean vancomycin renal clearance and were 3.20 liters/h and 29.7 liters respectively, while the clearance for patients on RRT was 0.15 liters/h. ECMO variables did not improve the final covariate model. We found that recommended dosing regimens for critically ill adult patients not on ECMO can be safely and effectively used in those on ECMO. Loading doses of at least 25 mg/kg followed by maintenance doses of 12.5-20 mg/kg every 12 h are associated with a 97-98% probability of efficacy and 11-12% probability of toxicity, in patients with normal renal function. Therapeutic drug monitoring along with reductions in dosing are warranted for patients with renal impairment and those with concomitant RRT. (This study is registered with the Australian New Zealand Clinical Trials Registry [ANZCTR] under number ACTRN12612000559819.).
Topics: Adult; Anti-Bacterial Agents; Australia; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Vancomycin
PubMed: 34633852
DOI: 10.1128/AAC.01377-21 -
Antimicrobial Agents and Chemotherapy Sep 2018Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on... (Clinical Trial)
Clinical Trial
Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for , but on average only 53% did for and 3% for , at the 15-mg/kg oral dose. For treating urinary tract infections caused by , oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).
Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Ciprofloxacin; Enterobacteriaceae; Female; Humans; Infant; Male; Prospective Studies; Pseudomonas aeruginosa; Staphylococcus aureus; Urinary Tract Infections
PubMed: 29987142
DOI: 10.1128/AAC.00517-18 -
Journal of Medical Entomology Feb 2019We tested the effect of the native container-dwelling predator Toxorhynchites rutilus on the codominant container-dwelling mosquitoes: native Aedes triseriatus and...
We tested the effect of the native container-dwelling predator Toxorhynchites rutilus on the codominant container-dwelling mosquitoes: native Aedes triseriatus and invasive Aedes japonicus. We established two predator treatments (predator, no predator) by removing T. rutilus from all containers, and stocking T. rutilus larvae (1/3.5 liters) in the predator treatment. Removal and stocking was repeated every 3 d and established significantly different predator abundances in both large and small containers. Repeated-measures analysis of variance (ANOVA) on standard samples showed larvae+pupae/liter of A. japonicus was greater without versus with predation, and this difference increased across samples. In contrast, repeated-measures ANOVA showed larvae+pupae/liter of A. triseriatus was statistically indistinguishable for predation treatments and was greater in small versus large containers. Thus, predation reduced invasive A. japonicus while having no detectable effect on A. triseriatus larvae and pupae. A final destructive census of pupae showed that predation reduced pupae/liter of both species, but this effect was greater and more consistent across container sizes for A. japonicus. Predator effects on abundances were not products of the nonlethal effect of predator avoidance by ovipositing females, as T. rutilus presence did not lead to reduced egg inputs by either Aedes, nor by Aedes spp. as a group. Effects of predation thus are best explained by differential success of developing larvae due to the greater lethal effect of T. rutilus on A. japonicus than on A. triseriatus. Thus, this system is consistent with the hypothesis that native predators can limit success and potential impacts of invasive mosquitoes.
Topics: Animals; Culicidae; Female; Introduced Species; Larva; Oviposition; Predatory Behavior; Pupa
PubMed: 30668785
DOI: 10.1093/jme/tjy196 -
Antimicrobial Agents and Chemotherapy 2014Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration...
Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.
Topics: Aged; Antiviral Agents; Critical Illness; Female; Ganciclovir; Hemodiafiltration; Humans; Male; Middle Aged; Monte Carlo Method
PubMed: 24145543
DOI: 10.1128/AAC.00892-13 -
Antimicrobial Agents and Chemotherapy Jan 2013This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous...
This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.
Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Colistin; Critical Illness; Drug Administration Schedule; Drug Dosage Calculations; Female; Hemodiafiltration; Humans; Male; Microbial Sensitivity Tests; Middle Aged
PubMed: 23147733
DOI: 10.1128/AAC.00985-12 -
Antimicrobial Agents and Chemotherapy Mar 1994Polyoxometalates are soluble mineral compounds formed principally of oxide anions and early transition metal cations. The polyoxometalates K12H2[P2W12O48].24H2O (JM...
Polyoxometalates are soluble mineral compounds formed principally of oxide anions and early transition metal cations. The polyoxometalates K12H2[P2W12O48].24H2O (JM 1591), K10[P2W18Zn4(H2O)2O68].20H2O (JM 1596), and [(CH3)3NH]8[Si2W18Nb6O77] (JM 2820) demonstrate potent antiviral activity against human immunodeficiency virus types 1 and 2, herpes simplex virus, and cytomegalovirus in vitro. The preclinical pharmacokinetics of these three compounds were characterized after single-dose intravenous administration of 50 mg/kg to rats. Plasma, urine, and feces were collected for 168 h, and polyoxometalate concentrations were determined by atomic emission. Serum protein binding was measured by equilibrium dialysis. All three compounds were highly bound to serum proteins in a concentration-dependent manner. Total and unbound concentrations of the three compounds in plasma declined in a triexponential manner with terminal half-lives of 246.0 +/- 127.0, 438.4 +/- 129.4, and 32.2 +/- 5.37 h (mean +/- standard deviation) for JM 1591, JM 1596, and JM 2820, respectively. Systemic clearances based on total concentrations in plasma were low, averaging 0.016 +/- 0.002, 0.015 +/- 0.002, and 0.018 +/- 0.003 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. The clearances of unbound compounds from plasma averaged 0.966 +/- 0.136, 0.050 +/- 0.005, and 0.901 +/- 0.165 liter/h/kg for JM 1591, JM 1596, and JM 2820, respectively. For JM 1596, the clearance of unbound compound from the kidneys was lower than the glomerular filtration rate (0.086 liter/h/kg), suggesting this polyoxometalate underwent renal tubular reabsorption. However, JM 1591 and JM 2820 appeared to undergo tubular secretion. The fraction of the dose recovered in urine was 11.5, 46.8, and 10.6% for JM 1591, JM 1596, and JM 2820, respectively. Approximately 5% of the dose of each polyoxometalate was recovered in feces. The steady-state volume of distribution based on total concentrations averaged 1.44 liters/kg for JM 1591, 2.39 liters/kg for JM 1596, and 0.59 liter/kg for JM 2820, indicating moderate to wide distribution throughout the body. All three compounds were detected in various tissues 1 week after single-dose administrations, with the highest levels found in the kidneys and liver. The results of this study indicate that the disposition of polyoxometalates is highly dependent on their molecular structure.
Topics: Animals; Antiviral Agents; Blood Proteins; Feces; Half-Life; Injections, Intravenous; Male; Organometallic Compounds; Protein Binding; Rats; Rats, Sprague-Dawley; Spectrophotometry, Atomic; Tungsten Compounds
PubMed: 8203845
DOI: 10.1128/AAC.38.3.504 -
Antimicrobial Agents and Chemotherapy Aug 2017To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is...
To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, -3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model.
Topics: Adolescent; Anti-Bacterial Agents; Bayes Theorem; Child; Child, Preschool; Drug Monitoring; Female; Gentamicins; Humans; Infant; Male; Nonlinear Dynamics; Pediatrics; Retrospective Studies; Software
PubMed: 28533244
DOI: 10.1128/AAC.00205-17 -
Antimicrobial Agents and Chemotherapy 2014The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal...
The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CLCR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC0-24) was 12.5 mg·h/liter for patients with normal renal function (CLCR, >80 ml/min), 14.7 mg·h/liter for patients with mild renal impairment (CLCR, 79 to 50 ml/min), and 17.9 mg·h/liter for patients with moderate renal impairment (CLCR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC0-48, 17.2 mg·h/liter) than for patients with normal renal function (median AUC0-48, 25.6 mg·h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function.
Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Deoxycytidine; Emtricitabine; Female; HIV Infections; Humans; Male; Middle Aged; Young Adult
PubMed: 24492366
DOI: 10.1128/AAC.02058-13 -
PloS One 2017This work evaluated the effect of cocoa pulp as a malt adjunct on the parameters of fermentation for beer production on a pilot scale. For this purpose, yeast isolated...
This work evaluated the effect of cocoa pulp as a malt adjunct on the parameters of fermentation for beer production on a pilot scale. For this purpose, yeast isolated from the spontaneous fermentation of cachaça (SC52), belonging to the strain bank of the State University of Feira de Santana-Ba (Brazil), and a commercial strain of ale yeast (Safale S-04 Belgium) were used. The beer produced was subjected to acceptance and purchase intention tests for sensorial analysis. At the beginning of fermentation, 30% cocoa pulp (adjunct) was added to the wort at 12°P concentration. The production of beer on a pilot scale was carried out in a bioreactor with a 100-liter capacity, a usable volume of 60 liters, a temperature of 22°C and a fermentation time of 96 hours. The fermentation parameters evaluated were consumption of fermentable sugars and production of ethanol, glycerol and esters. The beer produced using the adjunct and yeast SC52 showed better fermentation performance and better acceptance according to sensorial analysis.
Topics: Beer; Bioreactors; Cacao; Carbohydrates; Chromatography, High Pressure Liquid; Esters; Ethanol; Fermentation; Glycerol; Hydrogen-Ion Concentration; Pilot Projects; Saccharomyces cerevisiae; Solid Phase Microextraction; Temperature; Time Factors
PubMed: 28419110
DOI: 10.1371/journal.pone.0175677