Relationships between serum, intracellular, and infection site concentrations of macrolide and azalide antibiotics: A theoretical exploration of the concept of white blood cell drug delivery to infection sites

J. J. Schentag, A. Forrest, David E. Nix, C. H. Ballow

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1 Citation (Scopus)

Abstract

A new theoretical model is proposed to describe the contribution of white blood cell (WBC) drug delivery to the total amount of available macrolide or azalide antibiotic at the infection site. This model was based on the serum concentration versus time courses of azithromycin (an azalide) and erythromycin (a macrolide) and their respective tissue: serum ratios in WBCs and in other tissues. This infection site model also incorporates a pharmacokinetic evaluation of the time course of WBCs at infection sites during active infection and during resolution. The primary discoveries of this exercise were that tissue homogenate:serum ratios could be described for both antibiotics, and that both antibiotics could achieve mass balance of drug distribution among the various body sites in the absence of infection. In the presence of infection, drug delivery by WBCs was predicted to add about 10-fold greater amounts of drug than serum to local erythromycin concentrations, as the amount delivered by WBCs at a highly inflammatory (109 WBCs) site resulted in a 10-fold increase in the amount of erythromycin at the infection site. Drug delivery by WBCs was predicted to be even more important for azithromycin. In the presence of large numbers of WBCs (109 cells), local infection site azithromycin concentrations rose over 100-fold. The phenomenon of WBC delivery increased the area under the inhibitory time curve (AUIC) at infection sites to values in excess of the 125 threshold for activity. While this was of importance for both antibiotics, the contribution of WBC delivery to infection site AUIC was greater for azithromycin than for erythromycin. In summary, this theoretical model may account for the high degree of success of macrolides and particularly azalides at tissue infection sites in spite of their generally low serum concentrations. The property of WBC delivery may be an important contributor to the total antimicrobial action of these antibiotics.

Original languageEnglish (US)
Pages (from-to)137-146
Number of pages10
JournalAntiinfective Drugs and Chemotherapy
Volume14
Issue number2
StatePublished - 1996
Externally publishedYes

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Macrolides
Leukocytes
Anti-Bacterial Agents
Infection
Serum
Pharmaceutical Preparations
Azithromycin
Erythromycin
Theoretical Models
Catalytic Domain
Pharmacokinetics

Keywords

  • antibiotics
  • azithromycin
  • erythromycin
  • phagocyte delivery
  • pharmacokinetics
  • WBC delivery

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Relationships between serum, intracellular, and infection site concentrations of macrolide and azalide antibiotics: A theoretical exploration of the concept of white blood cell drug delivery to infection sites",
abstract = "A new theoretical model is proposed to describe the contribution of white blood cell (WBC) drug delivery to the total amount of available macrolide or azalide antibiotic at the infection site. This model was based on the serum concentration versus time courses of azithromycin (an azalide) and erythromycin (a macrolide) and their respective tissue: serum ratios in WBCs and in other tissues. This infection site model also incorporates a pharmacokinetic evaluation of the time course of WBCs at infection sites during active infection and during resolution. The primary discoveries of this exercise were that tissue homogenate:serum ratios could be described for both antibiotics, and that both antibiotics could achieve mass balance of drug distribution among the various body sites in the absence of infection. In the presence of infection, drug delivery by WBCs was predicted to add about 10-fold greater amounts of drug than serum to local erythromycin concentrations, as the amount delivered by WBCs at a highly inflammatory (109 WBCs) site resulted in a 10-fold increase in the amount of erythromycin at the infection site. Drug delivery by WBCs was predicted to be even more important for azithromycin. In the presence of large numbers of WBCs (109 cells), local infection site azithromycin concentrations rose over 100-fold. The phenomenon of WBC delivery increased the area under the inhibitory time curve (AUIC) at infection sites to values in excess of the 125 threshold for activity. While this was of importance for both antibiotics, the contribution of WBC delivery to infection site AUIC was greater for azithromycin than for erythromycin. In summary, this theoretical model may account for the high degree of success of macrolides and particularly azalides at tissue infection sites in spite of their generally low serum concentrations. The property of WBC delivery may be an important contributor to the total antimicrobial action of these antibiotics.",
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