Infect Chemother.  2014 Dec;46(4):219-225. 10.3947/ic.2014.46.4.219.

Interpretation of Epithelial Lining Fluid Concentrations of Antibiotics against Methicillin Resistant Staphylococcus aureus

Affiliations
  • 1Department of Internal Medicine, Inje University College of Medicine, Busan, Korea. smkimkor@yahoo.com
  • 2School of Pharmacy and Pharmaceutical Sciences, The University at Buffalo, Buffalo, New York, USA.

Abstract

Although antibiotics whose epithelial lining fluid (ELF) concentrations are reported high tend to be preferred in treatment of pneumonia, measurement of ELF concentrations of antibiotics could be misled by contamination from lysis of ELF cells and technical errors of bronchoalveolar lavage (BAL). In this review, ELF concentrations of anti-methicillin resistant Staphylococcus aureus (MRSA) antibiotics were interpreted considering above confounding factors. An equation used to explain antibiotic diffusion into CSF (cerebrospinal fluid) was adopted: ELF/free serum concentration ratio = 0.96 + 0.091 x ln (partition coefficient / molecular weight1/2). Seven anti-MRSA antibiotics with reported ELF concentrations were fitted to this equation to see if their ELF concentrations were explainable by the penetration capacity only. Then, outliers were modeled under the assumption of varying contamination from lysed ELF cells (test range 0-10% of ELF volume). ELF concentrations of oritavancin, telavancin, tigecycline, and vancomycin were well described by the diffusion equation, with or without additional impact from cell lysis. For modestly high ELF/free serum concentration ratio of linezolid, technical errors of BAL should be excluded. Although teicoplanin and iclaprim showed high ELF/free serum ratios also, their protein binding levels need to be cleared for proper interpretation. At the moment, it appears very premature to use ELF concentrations of anti-MRSA antibiotics as a relevant guide for treatment of lung infections by MRSA.

Keyword

Epithelial lining fluid; Methicillin-resistant Staphylococcus aureus; Bronchoalveolar lavage; Protein binding

MeSH Terms

Anti-Bacterial Agents*
Bronchoalveolar Lavage
Diffusion
Linezolid
Lung
Methicillin Resistance*
Methicillin-Resistant Staphylococcus aureus
Pneumonia
Protein Binding
Staphylococcus aureus*
Teicoplanin
Vancomycin
Anti-Bacterial Agents
Teicoplanin
Vancomycin

Figure

  • Figure 1 Plot of ELF/free serum concentration ratios of oritavancin, telavancin, tigecycline and vancomycin considering penetration capacity (constant K) and potential lysis of ELF cells. Low ratios of telavancin and vancomycin were considered to be related to their low penetration capacity. High ratios of oritavancin and tigecycline beyond their penetration capacity could be explained with contamination from lysed ELF cells within the range of the volume percentage of the cells (3-10%) in ELF. Celf, ELF concentration; Cfs, free serum concentration; K, constant K=0.96 + 0.091·ln (partition coefficient · molecular weight-1/2); AUCelf, AUC in ELF; AUCfs, free AUC in serum; ELF, epithelial lining fluid; AUC, area under the curve.

  • Figure 2 Plot of ELF/free serum concentration ratios of linezolid considering penetration capacity (constant K) and potential lysis of ELF cells. The modest ratio of linezolid could not be explained with either penetration capacity nor cell lysis. By the difference of the ratios depending on different techniques (linezolid 1, 2 vs. linezolid 3) it was considered that technical errors might be involved in the process of BAL. Celf, ELF concentration; Cfs, free serum concentration; K, constant K=0.96 + 0.091·ln (partition coefficient · molecular weight-1/2); AUCelf, AUC in ELF; AUCfs, free AUC in serum; ELF, epithelial lining fluid; AUC, area under the curve.

  • Figure 3 Plot of ELF/free serum concentration ratios of iclaprim and teicoplanin considering penetration capacity (constant K) and potential lysis of ELF cells. The ratios could not be explained with either penetration capacity nor cell lysis. Protein binding levels of the antibiotics need to be cleared for the proper interpretation, for biologically measured levels of their protein binding were negligible despite the reported high in vitro protein binding rates. Celf, ELF concentration; Cfs, free serum concentration; K, constant K=0.96 + 0.091·ln (partition coefficient · molecular weight-1/2); AUCelf, AUC in ELF; AUCfs, free AUC in serum; ELF, epithelial lining fluid; AUC, area under the curve.


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