A mathematical model-based analysis of the time-kill kinetics of ceftazidime/avibactam against Pseudomonas aeruginosa.

Objectives: To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems.

Methods: The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam. Ceftazidime's effect on the bacterial population was described as an enhancement of the death rate of the active population, with the effect of avibactam being to increase ceftazidime potency.

Potentiation of ceftazidime by avibactam against β-lactam-resistant Pseudomonas aeruginosa in an in vitro infection model.

Objectives: This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-β-lactam β-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method.

Methods: MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa .

Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats.

Background And Purpose: While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity.

Experimental Approach: Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30 mg·kg(-1) , p.

In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms.

Objectives: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles.

Methods: The MICs of aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L).

Bioanalytical method validation for the simultaneous determination of ceftazidime and avibactam in rat plasma.

Background: Combination therapies have gained momentum in the disease management strategies of various indications. While it is challenging and more time consuming to develop a combined analytical method, the strategy of simultaneous analysis offers significant advantages in terms of efficiency and cost-effectiveness.

Results: Due to a significant difference in efficacious dose for ceftazidime and avibactam, the calibration ranges validated in this paper were set to 0.

Improvement of the pharmacokinetics and in vivo antibacterial efficacy of a novel type IIa topoisomerase inhibitor by formulation in liposomes.

Several useful properties of liposome-based formulations of various existing antibacterial drugs have been reported. These properties include lower MICs, improved pharmacokinetics, lower toxicity, selective distribution to infected tissues, and enhanced in vivo efficacy. Here we report in vivo studies of a liposomal formulation of a member of a novel class of antibacterial type II topoisomerase inhibitors, others of which have progressed to early phases of clinical trials.

Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa.

The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P.

Utility of spatially-resolved atmospheric pressure surface sampling and ionization techniques as alternatives to mass spectrometric imaging (MSI) in drug metabolism.

Tissue distribution studies of drug molecules play an essential role in the pharmaceutical industry and are commonly undertaken using quantitative whole body autoradiography (QWBA) methods. The growing need for complementary methods to address some scientific gaps around radiography methods has led to increased use of mass spectrometric imaging (MSI) technology over the last 5 to 10 years. More recently, the development of novel mass spectrometric techniques for ambient surface sampling has redefined what can be regarded as "fit-for-purpose" for MSI in a drug metabolism and disposition arena.

Quantifying trifluoroacetic acid as a counterion in drug discovery by 19F NMR and capillary electrophoresis.

Drug discovery compounds are often isolated as salts of trifluoroacetate from preparative high performance liquid chromatography, which are then used for biological assays in order to assess their efficacy against the biochemical target of interest. It is, therefore, imperative to determine the TFA content in order to ascertain the correct formula weight and when required, to ensure that the TFA has been completely exchanged for another counterion in order to have superior pharmacokinetic properties and to avoid potential toxicity effects. In this paper, we present capillary electrophoresis and (19)F nuclear magnetic resonance methods for determining the TFA content of drug discovery compounds.

Capillary electrophoresis separation of a mixture of chitin and chitosan oligosaccharides derivatized using a modified fluorophore conjugation procedure.

A capillary electrophoresis (CE) method was developed for the simultaneous analysis of small chitin and chitosan oligosaccharides. For detection purposes, the oligomers were derivatized with 8-aminopyrene-1,3,6-trisulfonic acid (APTS), a well known fluorophore for oligosaccharides analysis. The detection was performed by laser-induced fluorescence (LIF) with an argon ion laser having an excitation wavelength of 488 nm and with emission monitored at 520 nm.