Interpretation of Antibiotic Concentration Ratios Measured in Epithelial Lining Fluid

Kiem, Sungmin; Schentag, Jerome J.

doi:10.1128/aac.00133-06

Cited by 238 publications

(289 citation statements)

References 104 publications

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“…The model training dataset was based on two previously reported systematic reviews of clinical studies quantifying concentrations of anti-infective agents (antibiotics, antifungals and associated agents such as β-lactamase inhibitors) in plasma and ELF (7,8). The original publications included in these two systematic reviews were considered to represent a complete overview of available literature on ELF lung concentrations reported for anti-infective agents up to 2011.…”

Section: Data Collection Extraction and Curation Proceduresmentioning

confidence: 99%

“…For the ELF concentrations we assumed that protein binding plays a negligible role since protein concentrations in the ELF are much lower than in plasma (23). an assumption also made by other investigators (7).…”

Section: Data Collection Extraction and Curation Proceduresmentioning

confidence: 99%

“…The alveolar membrane acts as a semi-permeable barrier due to the presence of tight junctions (5) and the presence of drug transporter proteins (6). This results in ELF concentrations that may be several folds lower or higher than the corresponding plasma concentration, as was nicely summarized by Kiem et al (7) and Rodvold et al (8). Therefore, the consideration of ELF concentrations during development of antibiotic agents for lung infections is of considerable importance.…”

Section: Introductionmentioning

confidence: 99%

“…A more recent and promising technique for measuring ELF concentrations is bronchoscopic microsampling (BMS), which allows for repeated measurement of concentrations over time (11). Considerable variability has been reported for ELF concentrations not only between subjects but also within subjects (7,8). Such variation can be related to the aforementioned methodological issues, the drug-distribution related pharmacokinetics (PK), and potentially other physiological disease related factors such as edema and potential effects of inflammation on membrane permeability.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

et al. 2015

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Purpose Obtaining pharmacologically relevant exposure levels of antibiotics in the epithelial lining fluid (ELF) is of critical importance to ensure optimal treatment of lung infections. Our objectives were to develop a model for the prediction of the ELF-plasma concentration ratio (EPR) of antibiotics based on their chemical structure descriptors (CSDs). Methods EPR data was obtained by aggregating ELF and plasma concentrations from historical clinical studies investigating antibiotics and associated agents. An elastic net regularized regression model was used to predict EPRs based on a large number of CSDs. The model was tuned using leave-one-drug-out cross validation, and the predictions were further evaluated using a test dataset. Results EPR data of 56 unique compounds was included. A high degree of variability in EPRs both between-and within drugs was apparent. No trends related to study design or pharmacokinetic factors could be identified. The model predicted 80% of the within-drug variability (R 2 WDV ) and 78.6% of drugs were within 3-fold difference from the observations. Key CSDs were related to molecular size and lipophilicity. When predicting EPRs for a test dataset the R 2 WDV was 75%. Conclusions This model is of relevance to inform dose selection and optimization during antibiotic drug development of agents targeting lung infections.

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Section: Data Collection Extraction and Curation Proceduresmentioning

confidence: 99%

Section: Data Collection Extraction and Curation Proceduresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

et al. 2015

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“…4. 32) The values for erythromycin and midekamaycin are from Tosti et al 33) and those for kitasamycin and cethromycin are from Tanaka et al 34) and Kiem et al 35) respectively. The values for clarithromycin, 16) azithromycin, 36) rokitamycin 26) and telithromycin 37) are from their respective interview forms.…”

Section: Fig 3 Effects Of Vitamin E and Macrolides On Hypotonic Hemomentioning

confidence: 99%

Protective Effects of Clarithromycin, a Lipophilic 14-membered Macrolide, on Hemolysis Induced by Lysophosphatidylcholine in Human Erythrocytes

Iwayama

Takashima

Ohtaki

et al. 2012

Jpn. J. Pharm. Health Care Sci.

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The Pharmacodynamics of Antimicrobial Agents

Martinez¹,

Toutain²,

Turnidge³

2013

Antimicrobial Therapy in Veterinary Medicine

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Interpretation of Antibiotic Concentration Ratios Measured in Epithelial Lining Fluid

Cited by 238 publications

References 104 publications

Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

Protective Effects of Clarithromycin, a Lipophilic 14-membered Macrolide, on Hemolysis Induced by Lysophosphatidylcholine in Human Erythrocytes

The Pharmacodynamics of Antimicrobial Agents

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