Due to the low level of resistance observed with daptomycin, this antibiotic has an important place in the treatment of severe Gram-positive infections. It is the first-in-class of the group of ...calcium-dependent, membrane-binding lipopeptides, and is a cyclic peptide constituted of 13 amino acids and an n-decanoyl fatty acid chain. The antibacterial action of daptomycin requires its complexation with calcium. Daptomycin is not absorbed from the gastrointestinal tract and needs to be administered parenterally. The distribution of daptomycin is limited (volume of distribution of 0.1 L/kg in healthy volunteers) due to its negative charge at physiological pH and its high binding to plasma proteins (about 90%). Its elimination is mainly renal, with about 50% of the dose excreted unchanged in the urine, justifying dosage adjustment for patients with renal insufficiency. The pharmacokinetics of daptomycin are altered under certain pathophysiological conditions, resulting in high interindividual variability. As a result, therapeutic drug monitoring of daptomycin may be of interest for certain patients, such as intensive care unit patients, patients with renal or hepatic insufficiency, dialysis patients, obese patients, or children. A target for the ratio of the area under the curve to the minimum inhibitory concentration > 666 is usually recommended for clinical efficacy, whereas in order to limit the risk of undesirable muscular effects the residual concentration should not exceed 24.3 mg/L.
An in-depth characterization of nanoparticle-doped optical fibers is crucial to understand the potential new functionalities of the engineered glass and thus their applicability fields. The high ...temperatures of the manufacturing process strongly affect the nanoparticle features, and therefore, their analysis is necessary after fiber drawing. However, the difficulties associated with the use of atomic resolution microscopies to analyze the nanoparticle features in the fiber core, mainly related to sample preparation and expensive costs, usually prevent their study. In this work, we overcome some of those limitations and demonstrate, for the first time, the suitability of structurally and microstructurally studying in detail nanocrystals contained in a fiber core of ∼10 μm by combining confocal Raman microscopy, Rayleigh light-scattering microscopy, and scanning electron microscopy (SEM). A thorough study of cubic-shaped and rod-shaped YPO4 nanocrystals contained in optical fibers reveals their crystallization in tetragonal (t) and monoclinic (m) structures, respectively. The symmetric (ν1) and asymmetric stretching (ν3) Raman modes display a different and remarkable red shift as particle size decreases in both types of nanocrystals, which in the case of the cubic-shaped nanocrystals is fitted to an exponential function along with a Raman peak broadening. Moreover, their Raman dependence vs temperature is evaluated up to 600 °C, observing a phonon softening that follows a linear behavior, which is discussed in detail. These findings add new insights to pure m-YPO4, which was unknown to date, and the REPO4 family and open up new avenues that can be extrapolated to other nanostructures incorporated into optical fiber cores, which will advance progress in the field of nanoparticle-doped optical fibers.
Metal-organic frameworks (MOFs) are recognized as ideal candidates for many applications such as gas sorption and catalysis. For a long time the properties of these materials were thought to ...essentially arise from their well-defined crystal structures. It is only recently that the importance of structural defects for the properties of MOFs has been evidenced. In this work, salt-assisted and liquid-assisted grinding were used to introduce defects in a copper-based MOF, namely HKUST-1. Different milling times and post-synthetic treatments with alcohols allow introduction of defects in the form of free carboxylic acid groups or reduced copper(
i
) sites. The nature and the amount of defects were evaluated by spectroscopic methods (FTIR, XPS) as well as TGA and NH
3
temperature-programmed desorption experiments. The negative impact of free -COOH groups on the catalytic cyclopropanation reaction of ethyl diazoacetate with styrene, as well as on the gravimetric CO
2
sorption capacities of the materials, was demonstrated. The improvement of the catalytic activity of carboxylic acid containing materials by the presence of Cu
I
sites was also evidenced.
Defective HKUST-1 was prepared by salt- or liquid-assisted grinding with post-synthetic treatments with alcohols. The defects identified as free carboxylic acid groups or reduced Cu(
i
) sites influence strongly gas storage and catalytic properties.
Optimal dosing for nebulized colistin methanesulfonate (CMS), the prodrug of colistin, is unknown. We describe the pulmonary and systemic pharmacokinetics of CMS and colistin following nebulization ...of 0.5 million IU (MIU) of CMS in ventilated patients.
Twelve critically ill patients received 0.5 MIU of CMS administered every 8 h as 30 min nebulizations. Blood samples were collected immediately before and until 8 h after first nebulization; mini-bronchoalveolar lavage (mini-BAL) was performed at 1 and 5 h or 3 and 8 h (six patients each) post-dose. Pharmacokinetic analysis was performed for CMS and colistin plasma concentrations using a non-compartmental method. ClinicalTrials.gov: NCT01060891.
After nebulization, CMS concentrations in epithelial lining fluid (ELF) were much higher (100- to 1000-fold) than those in plasma. Concentrations of colistin in ELF should be considered with caution because when <6 mg/L in BAL, colistin bound to mini-BAL devices. Nevertheless, CMS and colistin concentrations in ELF were much lower than expected from previous results with a 2 MIU dose. From CMS plasma pharmacokinetics it was shown that CMS systemic bioavailability was only slightly decreased for the 0.5 MIU dose compared with 2 MIU.
This study shows that CMS concentrations were much higher (100- to 1000-fold) in ELF than in plasma after a 0.5 MIU aerosol of CMS, but much lower (10-fold) than expected from previous results with a 2 MIU dose. Therefore, until new pharmacokinetic and pharmacodynamic assessments of the treatment of ventilator-associated pneumonia with nebulized CMS are performed, the 2 MIU dose should be preferred to the 0.5 MIU dose.
Purpose
Quantification of pharmacodynamic interactions is key in combination therapies, yet conventional checkerboard experiments with up to 10 by 10 combinations are labor-intensive. Therefore, this ...study provides optimized experimental rhombic checkerboard designs to enable an efficient interaction screening with significantly reduced experimental workload.
Methods
Based on the general pharmacodynamic interaction (GPDI) model implemented in Bliss Independence, a novel rhombic ‘dynamic’ checkerboard design with quantification of bacteria instead of turbidity as endpoint was developed. In stochastic simulations and estimations (SSE), the precision and accuracy of interaction parameter estimations and classification rates of conventional reference designs and the newly proposed rhombic designs based on effective concentrations (EC) were compared.
Results
Although a conventional rich design with 20-times as many combination scenarios provided estimates of interaction parameters with higher accuracy, precision and classification rates, the optimized rhombic designs with one natural growth scenario, three monotherapy scenarios per combination partner and only four combination scenarios were still superior to conventional reduced designs with twice as many combination scenarios. Additionally, the rhombic designs were able to identify whether an interaction occurred as a shift on maximum effect or EC50 with > 98%. Overall, effective concentration-based designs were found to be superior to traditional standard concentrations, but were more challenged by strong interaction sizes exceeding their adaptive concentration ranges.
Conclusion
The rhombic designs proposed in this study enable a reduction of resources and labor and can be a tool to streamline higher throughput in drug interaction screening.
Extreme synthesis conditions can lead to discover materials and phenomena that are unknown under standard synthesis laboratory conditions. The particularities of the optical fiber fabrication, such ...as extreme temperatures, quenching heat treatments and the pressure generated during fiber drawing, among others, can be leveraged to explore novel phenomena at the nanoscale when optical fibers are engineered by nanoparticle doping. In this work, we demonstrate that starting from tetragonal cubic-shaped YPO4 nanocrystals contained into a silica-based optical fiber core, with a silica-based glass composition slightly modified with Ge P, and Al, it is possible to nucleate isolated spherical-shaped SiO nanocrystals by controlling fiber drawing temperature. This work demonstrates the existence of crystalline SiO, discussing the possible formation mechanism in detail, which addes new knowledge to silicon oxide family. Moreover, we show the suitability of using SiO nanocrystals for fabricating Rayleigh scattering enhanced optical fibers that can be applied for distributed sensing applications.
Abstract
Background
Combination therapy can increase efficacy of antibiotics and prevent emergence of resistance. Ceftazidime/avibactam and fosfomycin may be empirically combined for this purpose, ...but a systematic and quantitative evaluation of this combination is needed.
Objectives
In this study, a systematic analysis of the pharmacodynamic interactions of ceftazidime/avibactam and fosfomycin in clinical and isogenic Escherichia coli strains carrying genes coding for several carbapenemases or ESBLs was performed and pharmacodynamic interactions were quantified by modelling and simulations.
Methods
Pharmacodynamic interactions were evaluated in ‘dynamic’ chequerboard experiments with quantification of viable bacteria in eight isogenic and six clinical E. coli strains. Additionally, supplemental time–kill experiments were performed and genomic analyses were conducted on representative fosfomycin-resistant subpopulations. Models were fitted to all data using R and NONMEM®.
Results
Synergistic drug interactions were identified for 67% of the clinical and 75% of the isogenic isolates with a mean EC50 reduction of >50%. Time–kill experiments confirmed the interactions and modelling quantified EC50 reductions up to 97% in combination and synergy prevented regrowth of bacteria by enhanced killing effects. In 9 out of 12 fosfomycin-resistant mutants, genomic analyses identified previously reported mutations.
Conclusions
The broad synergistic in vitro activity of ceftazidime/avibactam and fosfomycin confirms the potential of the application of this drug combination in clinics. The substantial reduction of the EC50 in combination may allow use of lower doses or treatment of organisms with higher MIC values and encourage further research translating these findings into the clinical setting.
ABSTRACT
In contrast to the checkerboard method, bactericidal experiments time-kill curves (TKCs) allow an assessment of pharmacodynamic (PD) interactions over time. However, TKCs in combination pose ...interpretation problems. The objective of this study was to characterize the PD interaction over time between ceftazidime/avibactam (CZA) and colistin (CST) using TKC against four multidrug-resistant
Klebsiella pneumoniae
susceptible to both antibiotics and expressing a widespread carbapenemase determinant KPC-3.
In vitro
TKCs were performed and analyzed using pharmacokinetic/pharmacodynamic (PKPD) modeling. The general pharmacodynamic interaction model was used to characterize PD interactions between drugs. The 95% confidence intervals (95%CIs) of the expected additivity and of the observed interaction were built using parametric bootstraps and compared to evaluate the
in vitro
PD interaction over time. Further simulations were conducted to investigate the effect of the combination at varying concentrations typically observed in patients. Regrowth was observed in TKCs at high concentrations of drugs alone from 4 to 32× minimum inhibitory concentrations (MIC), while the combination systematically prevented the regrowth at concentrations close to the MIC. Significant synergy or antagonism were observed under specific conditions but overall 95%CIs overlapped widely over time indicating an additive interaction between antibiotics. Moreover, simulations of typical PK profile at standard dosages indicated that the interaction should be additive in clinical conditions. The nature of the PD interaction varied with time and concentration in TKC. Against the four
K. pneumoniae
isolates, the bactericidal effect of CZA + CST combination was predicted to be additive and to prevent the emergence of resistance at clinical concentrations.
Optimal dosing for nebulized gentamicin is unknown. We compared the pulmonary and systemic pharmacokinetics (PK) of gentamicin following intravenous and nebulized administration in mechanically ...ventilated patients.
Twelve critically ill male patients with ventilator-associated pneumonia received a 30 min intravenous infusion of 8 mg/kg gentamicin , followed 48 h afterwards by the same dose nebulized. Blood samples were collected immediately before and until 24 h after intravenous and nebulized administration; mini-bronchoalveolar lavages (mini-BALs) were performed at 3 and 7 h or 5 and 10 h (six patients each) after each intravenous and nebulized administration. The PK analysis was conducted using a population approach.
After intravenous administration, concentrations of gentamicin measured in epithelial lining fluid (ELF) were very variable, and overall in the same range of magnitude (from 0.3 to 28 mg/L) as in plasma. After nebulization, gentamicin concentrations were much higher (∼3800-fold) in ELF than in plasma. The average systemic bioavailability of nebulized gentamicin was estimated to be 5%, with considerable inter-individual variability. Compared with intravenous administration, after nebulization the exposure (expressed as AUC) to gentamicin was 276-fold greater in ELF and 18-fold lower in plasma.
Compared with intravenous administration, nebulization of gentamicin in patients with ventilator-associated pneumonia provides higher pulmonary concentrations and lower systemic concentrations but the inter-individual variability is large.
We demonstrate laser induced cooling in ytterbium doped silica (SiO
) glass with alumina, yttria co-doping (GAYY-Aluminum: Yttrium: Ytterbium Glass) fabricated using the modified chemical vapour ...deposition (MCVD) technique. A maximum temperature reduction by - 0.9 K from room temperature (296 K) at atmospheric pressure was achieved using only 6.5 W of 1029 nm laser radiation. The developed fabrication process allows us to incorporate ytterbium at concentration of 4 × 10
ions/m
which is the highest value reported for laser cooling without clustering or lifetime shortening, as well as to reach a very low background absorptive loss of 10 dB/km. The numerical simulation of temperature change versus pump power well agrees with the observation and predicts, for the same conditions, a temperature reduction of 4 K from room temperature in a vacuum. This novel silica glass has a high potential for a vast number of applications in laser cooling such as radiation-balanced amplifiers and high-power lasers including fiber lasers.
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