Clinical Pharmacokinetics of Inhaled Antimicrobials

Roberts, Jessica K.; Yellepeddi, Venkata K.; Sherwin, Catherine M.T.

doi:10.1007/s40262-015-0250-x

Cited by 20 publications

(16 citation statements)

References 176 publications

(222 reference statements)

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“…Following deposition, the absorption rate of inhaled drugs is related to the epithelium membrane's permeability, surface area, and drug concentration in mucosal fluids [71]. It is possible to control the concentration of the drug in mucosal fluids by controlling the rate of dissolution or release from a dry particle deposited in the lung.…”

Section: Control Of the Appearance Rate Of Fqs In Pulmonary Elf: Contmentioning

confidence: 99%

“…Accordingly, low water-soluble drugs that have limited lung absorption by their dissolution rate have a prolonged elimination half-life and increased average residence time in the lung [56]. For example, the poorly soluble antifungal agent amphotericin B can persist in the lungs for several days after inhalation [71]. Often, in this case, the plasma concentration profile of the drug is also changed after the inhalation of dry powder compared to after nebulization of a solution or IV administration.…”

Section: Control Of the Appearance Rate Of Fqs In Pulmonary Elf: Contmentioning

confidence: 99%

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Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Brillault

Tewes

2020

Pharmaceutics

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Pulmonary drug delivery is a promising strategy to treat lung infectious disease as it allows for a high local drug concentration and low systemic side effects. This is particularly true for low-permeability drugs, such as tobramycin or colistin, that penetrate the lung at a low rate after systemic administration and greatly benefit from lung administration in terms of the local drug concentration. However, for relatively high-permeable drugs, such as fluoroquinolones (FQs), the rate of absorption is so high that the pulmonary administration has no therapeutic advantage compared to systemic or oral administration. Formulation strategies have thus been developed to decrease the absorption rate and increase FQs’ residence time in the lung after inhalation. In the present review, some of these strategies, which generally consist of either decreasing the lung epithelium permeability or decreasing the release rate of FQs into the epithelial lining fluid after lung deposition, are presented in regards to their clinical aspects.

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Section: Control Of the Appearance Rate Of Fqs In Pulmonary Elf: Contmentioning

confidence: 99%

Section: Control Of the Appearance Rate Of Fqs In Pulmonary Elf: Contmentioning

confidence: 99%

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Brillault

Tewes

2020

Pharmaceutics

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“…However, we are unaware of any data on the interstitial space fluid pharmacokinetics of nebulized antibiotics. 15 As there are no data of the lung pharmacokinetics of different sampling and administration techniques, data from noninfected models can provide valuable mechanistic insights. Rat and rabbit model-based studies provide some data on the pharmacokinetics of nebulized and IV tobramycin.…”

Section: Editor's Perspectivementioning

confidence: 99%

Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model

et al. 2019

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Pseudomonasvaeruginosa and other Gram-negative organisms occurs frequently, 1 and is associated with significant morbidity and mortality. 2 Drugs from the aminoglycoside class, such as tobramycin, are recommended for the treatment of ventilator-associated pneumonia 3 and are effective against numerous Gram-negative organisms including P. aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumanii. 4 Despite systemic antibiotic therapy, therapeutic failure is common. 5 One reason for this lack of effect could be poor lung penetration due to low lung epithelial lining aBStraCt Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P < 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P < 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.

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“…Many inhaled antibiotics are hydrophilic and have a low molecular mass, making them easily systemically absorbed and eliminated after inhalation (61). Low solubility (high hydrophobicity) is required to decrease the dissolution rate and prolong lung surface contact before systemic absorption.…”

Section: Particle Engineeringmentioning

confidence: 99%

Inhaled Antibiotics for Gram-Negative Respiratory Infections

et al. 2016

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SUMMARYGram-negative organisms comprise a large portion of the pathogens responsible for lower respiratory tract infections, especially those that are nosocomially acquired, and the rate of antibiotic resistance among these organisms continues to rise. Systemically administered antibiotics used to treat these infections often have poor penetration into the lung parenchyma and narrow therapeutic windows between efficacy and toxicity. The use of inhaled antibiotics allows for maximization of target site concentrations and optimization of pharmacokinetic/pharmacodynamic indices while minimizing systemic exposure and toxicity. This review is a comprehensive discussion of formulation and drug delivery aspects,in vitroand microbiological considerations, pharmacokinetics, and clinical outcomes with inhaled antibiotics as they apply to disease states other than cystic fibrosis. In reviewing the literature surrounding the use of inhaled antibiotics, we also highlight the complexities related to this route of administration and the shortcomings in the available evidence. The lack of novel anti-Gram-negative antibiotics in the developmental pipeline will encourage the innovative use of our existing agents, and the inhaled route is one that deserves to be further studied and adopted in the clinical arena.

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Clinical Pharmacokinetics of Inhaled Antimicrobials

Cited by 20 publications

References 176 publications

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model

Inhaled Antibiotics for Gram-Negative Respiratory Infections

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