scholarly journals Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats. 4. Aztreonam

2016 ◽  
Vol 60 (5) ◽  
pp. 3196-3198 ◽  
Author(s):  
Sandrine Marchand ◽  
Nicolas Grégoire ◽  
Julien Brillault ◽  
Isabelle Lamarche ◽  
Patrice Gobin ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Low Permeability ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time ◽  
High Area ◽  
Plasma Concentration Time Curve ◽  
Pharmacokinetics In Rats

ABSTRACTThe aim of this study was to determine aztreonam (ATM) membrane permeability using Calu-3 cells and its plasma and pulmonary epithelial lining fluid (ELF) pharmacokinetics in rats after intratracheal nebulization and intravenous administration (15 mg · kg−1). ATM exhibits low Calu-3 permeability (0.07 ± 0.02 × 10−6cm · s−1), and a high area under the ELF/unbound plasma concentration time curve between 0 and infinity (AUCELF/AUCu,plasma) ratio of 1,069 was observed after nebulization in rats. These results confirm that ATM is a low-permeability molecule and a good candidate for nebulization.

scholarly journals Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 6. Aminoglycosides

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sandrine Marchand ◽  
Matthieu Boisson ◽  
Shachi Mehta ◽  
Christophe Adier ◽  
Olivier Mimoz ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Antimicrobial Agents ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time

ABSTRACT Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.

scholarly journals Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 5. Oseltamivir Carboxylate

2016 ◽  
Vol 60 (8) ◽  
pp. 5085-5087 ◽  
Author(s):  
Danilo Cesar Galindo Bedor ◽  
Sandrine Marchand ◽  
Isabelle Lamarche ◽  
Julian Laroche ◽  
Davi Pereira de Santana ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Area Under The Curve ◽  
Pulmonary Delivery ◽  
Epithelial Lining ◽  
Oseltamivir Carboxylate ◽  
Epithelial Lining Fluid

ABSTRACTThe aim of this study was to determine the biopharmaceutical characteristics of oseltamivir carboxylate (OC) after pulmonary delivery. After OC bolus and intratracheal nebulization (NEB) in rats, blood was collected and bronchoalveolar lavages (BALs) were performed. Epithelial lining fluid (ELF) concentrations were estimated from BAL fluid. The area under the curve (AUC) ratio for ELF to plasma was 842 times higher after NEB than after intravenous (i.v.) administration, indicating that OC nebulization offers a biopharmaceutical advantage over i.v. administration.

scholarly journals In Vivo Pharmacodynamic Evaluation of Omadacycline against Staphylococcus aureus in the Neutropenic Mouse Pneumonia Model

2019 ◽  
Vol 64 (2) ◽  
Author(s):  
Alexander J. Lepak ◽  
Miao Zhao ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
David R. Andes
Keyword(s):  
Staphylococcus Aureus ◽  
Therapeutic Effect ◽  
Bacterial Pneumonia ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Content Type ◽  
Concentration Time ◽  
Mrsa Strains

ABSTRACT Omadacycline is an effective therapy for community-acquired bacterial pneumonia (CABP). Given its potent activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA), we sought to determine the pharmacodynamic activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with a therapeutic effect in the neutropenic mouse pneumonia model against 10 MSSA/MRSA strains. The area under the concentration-time curve (AUC)/MIC associated with 1-log kill was noted at 24-h epithelial lining fluid (ELF) and plasma AUC/MIC exposures of ∼2 (ELF range, <0.93 to 19; plasma range, <1.06 to 17) and 2-log kill was noted at 24-h ELF and plasma AUC/MIC exposures of ∼12 (ELF range, 2.5 to 130; plasma range, 3.5 to 151).

scholarly journals Penetration of GSK1322322 into Epithelial Lining Fluid and Alveolar Macrophages as Determined by Bronchoalveolar Lavage

2013 ◽  
Vol 58 (1) ◽  
pp. 419-423 ◽  
Author(s):  
Odin J. Naderer ◽  
Keith A. Rodvold ◽  
Lori S. Jones ◽  
John Z. Zhu ◽  
Chester L. Bowen ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Alveolar Macrophages ◽  
Bacterial Infections ◽  
Time Course ◽  
Respiratory Pathogens ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time

ABSTRACTGSK1322322 is a potent peptide deformylase inhibitor within vitroandin vivoactivity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0–τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of epithelial lining fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0–τfor ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0–τratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered atClinicalTrials.govunder registration number NCT01610388.)

scholarly journals Pharmacodynamics of Levofloxacin in a Murine Pneumonia Model of Pseudomonas aeruginosa Infection: Determination of Epithelial Lining Fluid Targets

2009 ◽  
Vol 53 (8) ◽  
pp. 3325-3330 ◽  
Author(s):  
Arnold Louie ◽  
Christine Fregeau ◽  
Weiguo Liu ◽  
Robert Kulawy ◽  
G. L. Drusano
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Single Agent ◽  
Time Profile ◽  
Epithelial Lining ◽  
Time Data ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Mutational Frequency ◽  
Concentration Time ◽  
Low Exposure

ABSTRACT The dose choice for Pseudomonas aeruginosa remains a matter of debate. The actual exposure targets required for multilog killing of organisms at the primary infection site have not been delineated. We studied Pseudomonas aeruginosa PAO1 using a murine model of pneumonia. We employed a large mathematical model to fit all the concentration-time data in plasma and epithelial lining fluid (ELF) as well as colony counts in lung simultaneously for all drug doses. Penetration into ELF was calculated to be approximately 77.7%, as indexed to the ratio of the area under the concentration-time curve for ELF (AUCELF) to the AUCplasma. We determined the ELF concentration-time profile required to drive a stasis response as well as 1-, 2-, or 3-log10(CFU/g) kill. AUC/MIC ratios of 12.4, 31.2, 62.8, and 127.6 were required to drive these bacterial responses. Emergence of resistance was seen only at the two lowest doses (three of five animals at 50 mg/kg [body weight] and one of five animals at 100 mg/kg). The low exposure targets were likely driven by a low mutational frequency to resistance. Bridging to humans was performed using Monte Carlo simulation. With a 750-mg levofloxacin dose, target attainment rates fell below 90% at 4 mg/liter, 1 mg/liter, and 0.5 mg/liter for 1-, 2-, and 3-log kills, respectively. Given the low exposure targets seen with this strain, we conclude that levofloxacin at a 750-mg dose is not adequate for serious Pseudomonas aeruginosa pneumonia as a single agent. More isolates need to be studied to make these observations more robust.

scholarly journals Penetration of Meropenem into Epithelial Lining Fluid of Patients with Ventilator-Associated Pneumonia

2011 ◽  
Vol 55 (4) ◽  
pp. 1606-1610 ◽  
Author(s):  
T. P. Lodise ◽  
F. Sorgel ◽  
D. Melnick ◽  
B. Mason ◽  
M. Kinzig ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Compartment Model ◽  
Ventilator Associated Pneumonia ◽  
Epithelial Lining ◽  
Time Data ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Time Profiles ◽  
Concentration Time

ABSTRACTAntibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of β-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUCELF/AUCplasmaratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUCELF/AUCplasmaratio. The range of AUCELF/AUCplasmapenetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria likePseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

scholarly journals Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 3. Tobramycin

2015 ◽  
Vol 59 (10) ◽  
pp. 6646-6647 ◽  
Author(s):  
Sandrine Marchand ◽  
Nicolas Grégoire ◽  
Julien Brillault ◽  
Isabelle Lamarche ◽  
Patrice Gobin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Antimicrobial Agents ◽  
Area Under The Curve ◽  
Bolus Administration ◽  
Tandem Mass ◽  
Epithelial Lining ◽  
Epithelial Lining Fluid ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass

ABSTRACTThe aim of this study was to determine the biopharmaceutical characteristics of tobramycin (TOB) after nebulization in rats. TOB was administered by intravenous (i.v.) bolus or intratracheal nebulization (3 mg · kg−1), and concentrations were determined in plasma and epithelial lining fluid (ELF) by liquid chromatography-tandem mass spectrometry. The ratio of the TOB concentration in ELF to the plasma area under the curve (AUC) was more than 200 times as high after NEB as after i.v. bolus administration, indicating that TOB nebulization offers a biopharmaceutical advantage over i.v. administration.

scholarly journals Telavancin Penetration into Human Epithelial Lining Fluid Determined by Population Pharmacokinetic Modeling and Monte Carlo Simulation

2008 ◽  
Vol 52 (7) ◽  
pp. 2300-2304 ◽  
Author(s):  
Thomas P. Lodise ◽  
Mark Gotfried ◽  
Steven Barriere ◽  
George L. Drusano
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Pharmacokinetic Data ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time

ABSTRACT Telavancin is an investigational bactericidal lipoglycopeptide with a multifunctional mechanism of action, as demonstrated against methicillin-resistant Staphylococcus aureus. While the plasma pharmacokinetics have been described, the extent of the penetration of the drug into the lung, measured by the epithelial lining fluid (ELF), remains unknown. Population modeling and Monte Carlo simulation were employed to estimate the penetration of telavancin into ELF. Plasma and ELF pharmacokinetic data were obtained from 20 healthy volunteers, and the pharmacokinetic samples were assayed by a validated liquid chromatography-tandem mass spectrometry technique. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified in a population pharmacokinetic analysis (BigNPAG). Monte Carlo simulation of 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) for the drug in ELF (AUCELF) and for the free drug in plasma (free AUCplasma) from zero to infinity after a single dose. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations in plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. The median AUCELF/free AUCplasma penetration ratio was 0.73, and the 25th and 75th percentile value ratios were 0.43 and 1.24, respectively. In uninfected lung tissue, the median AUCELF is approximately 75% of the free AUCplasma.

scholarly journals Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin

2022 ◽  
Author(s):  
Zoe Oesterreicher ◽  
Sabine Eberl ◽  
Beatrix Wulkersdorfer ◽  
Peter Matzneller ◽  
Claudia Eder ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Bronchoalveolar Lavage ◽  
Therapeutic Dose ◽  
Subcutaneous Tissue ◽  
Epithelial Lining ◽  
Clinical Trial Registration ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Concentration Time ◽  
Drug Concentrations

Abstract Background and Objective In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid. Methods Healthy subjects received a single intravenous bolus injection of a microdose of [14C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [14C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography–tandem mass spectrometry. Results The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration–time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration–time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration–time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin. Conclusions Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies. Clinical Trial Registration ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).

scholarly journals Pharmacodynamic Characterization of Ceftobiprole in Experimental Pneumonia Caused by Phenotypically Diverse Staphylococcus aureus Strains

2008 ◽  
Vol 52 (7) ◽  
pp. 2389-2394 ◽  
Author(s):  
Somvadee Laohavaleeson ◽  
Pamela R. Tessier ◽  
David P. Nicolau
Keyword(s):  
Staphylococcus Aureus ◽  
Dose Range ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Phenotypic Profile ◽  
Concentration Time ◽  
Mrsa Strains ◽  
Hospital Acquired ◽  
Free Plasma

ABSTRACT Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 μg/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log10 CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED80), ED50, and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to β-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.

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