Cefepime precision dosing tool: From Standard to Precise Dose Using Nonparametric Population Pharmacokinetics

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate cefepime population pharmacokinetic (PK) model and integrate into precision dosing tool for implementation. Two datasets (680 patients) were used to build cefepime PK model in Pmetrics, and three datasets (34 patients) were used for the validation. A separate application dataset (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 hr −1 (adults) and 0.96 hr −1 (pediatrics), central volume of distribution 13.85 L, and rate of transfer from the central to the peripheral compartments 1.22 hr −1 and from the peripheral to the central compartments 1.38 hr −1 . After integration in BestDose, the observed vs. predicted cefepime concentration fit using the application dataset was excellent (R 2 >0.98) and the median difference between observed and what BestDose predicted in a second occasion was 4%. For OID, cefepime 0.5-1g 4-hour infusion q8-24hr with CrCl<70 mL/min was needed to achieve a target range of free trough:MIC 1-4 at MIC 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation and the median concentration prediction bias was 4%. OID algorithm was provided.

Climate Change Impact On Flood Runoff Over Lake Baikal Catchment

Water level and distribution of dissolved and suspended matter of Lake Baikal are strongly affected by river inflow during rain-driven floods. This study analyses river flow changes at 44 streamflow gauges and related precipitation, evaporation, potential evaporation and soil moisture obtained from ERA5-Land dataset. Based on Sen-Slope trend estimator, Mann–Kendall non-parametric test, and using dominant analyses we estimated influence of meteorological parameters on river flow during 1979-2019. Using ridge-regression we found significant relationships between precipitation elasticity of river flow and catchments features. Half of the gauges in eastern part of Selenga river basin showed a significant decreasing trend of average and maximum river flow (up to -2.9%/year). No changes in central volume date of flood flow have been found. A reduction in rainfall amounts explains more than 60% of runoff decline. Decrease in evaporation is observed where precipitation decrease is 0.8%/y or more. Catchments where the precipitation trends are not as substantial are associated with increasing evaporation as a result of the increase of potential evaporation. Negative trends of precipitation are accompanied by negative trends of soil moisture. Finally, the study reveals sensitivity of the catchments with steep slopes in humid area to precipitation change.

Population pharmacokinetics of cefotaxime in intensive care patients

Purpose To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. Methods This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. Results A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. Conclusion A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations.Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation.Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin’s lymphoma (NHL).Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

Reply to Béranger et al., “Integration of Continuous Renal Replacement Therapy in a Meropenem Population Pharmacokinetics Model in Critically Ill Children”

We welcome Béranger et al.’s response to our recent publication (1), and we agree that the effect of continuous renal replacement therapy (CRRT) on pharmacokinetic parameters for meropenem (MEM) should be discussed. As Béranger et al. pointed out, extracorporeal membrane oxygenation (ECMO) was probably a component of the CRRT covariate, and it may have contributed to the increase in central volume of distribution. In fact, the circuit priming volume for ECMO can be several times higher than the pediatric patient’s blood volume, and hemodilution effect is inversely related to age (2).…

Pharmacokinetic and Pharmacodynamic Profiling of Minocycline for Injection Following a Single Infusion in Critically Ill Adults in a Phase IV Open-Label Multi-Center Study (ACUMIN)

Intravenous (IV) minocycline is increasingly used to treat infections caused by multi-drug resistant (MDR)-Acinetobacter baumannii. Despite being approved nearly 50 years ago, published information on its pharmacokinetic (PK) prolife is limited. This multi-center study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of IV minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200 mg IV dose of minocycline. Plasma PK samples were collected pre-dose and 1, 4, 12, 24, 36, and 48 hours after initiation of minocycline. Total and unbound minocycline concentrations were determined at each timepoint. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (fAUC:MIC of 12 and 18, respectively) were evaluated. A two-compartment population PK model with zero-order IV input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area [associated with central volume of distribution] and albumin (associated with fub). In the PK-PD target attainment analyses, minocycline 200 mg IV Q12H was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values ≥ 1 mg/L. These findings cast uncertainty on the appropriateness of the current minocycline FDA susceptibility breakpoints and suggest that clinicians should strongly consider only combination antibiotic therapy with IV minocycline for all patients with serious Acinetobacter sp. infections.

THE DNEPER UKRAINE TRADITION IN THE SACRED ARCHITECTURE OF DON REGION IN THE 18TH CENTURY

On the basis of historical graphic materials analysis, a number of Don region sacral objects were identified as those whose style and character are undoubtedly connected with the traditions of Dnieper Ukraine architecture. The influence of the Dnieper region architecture in this region is mainly associated with the main military cathedral in Cherkassk (now Starocherkassk), but, the presented materials shows a much wider scale of this phenomenon within the framework of wooden construction. Has been ascertained, that Dnieper architectural tradition is present in the whole territory of the Don region, and not only in those close to Zaporizhia and Slobozhanshchyna (Sloboda Ukraine). It is characterized by the combination of planning "octagons" (“vosmeryk”) on the principles of axial and centric symmetry, pyramid composition, accentuation of the central volume by the highest dome and more. Characteristic differences include some deviations from symmetry and the presence of a ground elevation. It is noted that among the whole complex of objects related to the Ukrainian cultural influence in the present territories of the Russian Federation (Kuban, Starodub region, East Sloboda Ukraine, Siberia, etc.), the Don region is the least researched for the identification and analysis of architectural objects in the solutions of which are traced to the Dnieper Ukraine signs. This is due primarily to the fact that, with the exception of a few stone ones, such objects ceased to exist during the nineteenth century, being replaced by new structures that has a completely different style. Since such buildings ceased to exist by the end of the nineteenth century, it has been determined that the prospective areas of further research are the study of graphic materials and documents, photographs, memories and more. Also important is the discovery of data pertaining to construction in the Don region before the eighteenth century, when its ties with the Dnieper and especially Zaporizhzhia were no less close.

A Pilot Study using the Compensatory Reserve Index to evaluate individuals with Postural Orthostatic Tachycardia syndrome

Purpose:The diagnosis of Postural Orthostatic Tachycardia syndrome traditionally involves orthostatic vitals evaluation. The Compensatory Reserve Index is a non-invasive, FDA-cleared algorithm that analyses photoplethysmogram waveforms in real time to trend subtle waveform features associated with varying degrees of central volume loss, from normovolemia to decompensation. We hypothesised that patients who met physiologic criteria for Postural Orthostatic Tachycardia syndrome would have greater changes in Compensatory Reserve Index with orthostatic vitals.Methods:Orthostatic vitals and Compensatory Reserve Index values were assessed in individuals previously diagnosed with Postural Orthostatic Tachycardia syndrome and healthy controls aged 12–21 years. Adolescents were grouped for comparison based on whether they met heart rate criteria for Postural Orthostatic Tachycardia syndrome (physiologic Postural Orthostatic Tachycardia syndrome).Results:Sixty-one patients were included. Eighteen percent of patients with an existing Postural Orthostatic Tachycardia syndrome diagnosis met heart rate criteria, and these patients had significantly greater supine to standing change in Compensatory Reserve Index (0.67 vs. 0.51; p<0.001). The optimal change in Compensatory Reserve Index for physiologic Postural Orthostatic Tachycardia syndrome was 0.60. Patients with physiologic Postural Orthostatic Tachycardia syndrome were more likely to report previous diagnoses of anxiety or depression (p = 0.054, 0.042).Conclusion:An accurate diagnosis of Postural Orthostatic Tachycardia syndrome may be confounded by related comorbidities. Only 18% (8/44) of previously diagnosed Postural Orthostatic Tachycardia syndrome patients met heart rate criteria. Findings support the utility of objective physiologic measures, such as the Compensatory Reserve Index, to more accurately identify patients with true autonomic dysfunction.

An Investigation Into the Robustness of a Crystal Plasticity Finite Element Model

A crystal plasticity model has been developed for describing the plastic and viscoplastic behaviour of 316H stainless steel. The model has been used successfully to predict the macroscopic response of the material for monotonic and cyclic loading, however the robustness of the model is now being scrutinised to ensure that it captures the underlying mechanisms and local meso-scale deformation characteristics correctly. In order to look at this in more detail, the model has been scripted to allow simulation of diffraction studies on the grains. This is being used to compare the simulation output with neutron and synchrotron experiments. A theoretical study has been completed which adjusts the values of each material parameter within the crystal plasticity finite element (CPFE) framework in isolation to analyse the effect each has upon the shape of the hysteresis loop and how this relates to predictions. A further study had been conducted to investigate the amount of scatter that is produced by altering the initial microstructure of a relatively small volume. The results show that changing the initial microstructure has a negligible effect on the subsequent stress-strain response. This indicates the influence that the grain morphology will have upon the diffraction measurements and that there is no need to consider this further when testing small specimens. To conclude this investigation two further aspects of the model have being scrutinised; the effects of constraining boundary conditions and altering the local environment of a single grain, again to explore the influences which these may have on diffraction studies. The plane boundaries of the volume are currently fixed at zero displacement which will influence the local grains on these boundaries as they are over constrained, but should not alter the overall stress-strain response. To investigate this, grains within the model that have boundary conditions applied have be discarded from the final results to leave the response from the central volume that should be free of the boundary condition effects. The results show that the macroscopic response of the bulk volume and the central volume are very similar but when the individual grain family responses are analysed, it can be seen that the boundary condition do alter the response of the representative volume element (RVE). To analyse how the local environment surrounding a single grain affects its stress-strain response, a centrally located grain will be selected and kept constant while the orientation of the surrounding grains are randomly altered. It has been found that changing the local environment surrounding a single grain will impact the stress-strain response seen by that grain.