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Pharmacokinetics and lung distribution of macrolide antibiotics in sepsis model rats

Shinji Kobuchi¹, Akihiro Fujita¹, Akihito Kato¹

¹Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems

|August 20, 2019

Abstract:

Recent studies have shown azithromycin-specific clinical efficacy against macrolide-resistant strains of Streptococcus pneumoniae, despite the low susceptibility of the bacteria in vitro. This discrepancy complicates dosing and selection for treatment of macrolide-resistant strains. Although phagocyte delivery of azithromycin to inflamed tissues is considered a possible factor for clinical efficacy, there is a lack of sufficient evidence, and other pharmacokinetic factors under systemic inflammation may contribute.The concentrations of azithromycin, clarithromycin and erythromycin in the plasma and buffy coat were determined in normal and sepsis model rats. Furthermore, we compared the transport of the drug into the lung.The levels of all three macrolides in the buffy coat were higher than the levels in the plasma, and lower leukocyte counts in plasma were observed in septic rats, suggesting accumulation of the drugs per leukocyte was increased. The concentrations in the lung tissue of septic rats at each sampling time were the same as those in normal rats, and azithromycin-specific long-term stasis in the lung was evident.These results suggest that both the phagocyte delivery and the stasis of azithromycin in the lung could contribute to its clinical efficacy in treating infections caused by macrolide-resistant strains.

Insights

Azithromycin shows clinical effectiveness against resistant bacteria, even with low in vitro susceptibility. This study suggests drug accumulation in immune cells and sustained presence in lung tissue contribute to its efficacy.

Area of Science:

Pharmacology
Infectious Diseases
Microbiology

Background:

Macrolide-resistant *Streptococcus pneumoniae* presents treatment challenges.
Azithromycin demonstrates clinical efficacy despite low in vitro susceptibility.
Phagocyte delivery and pharmacokinetic factors in inflammation may explain this discrepancy.

Purpose of the Study:

To investigate the pharmacokinetic behavior of azithromycin, clarithromycin, and erythromycin in normal and sepsis model rats.
To compare drug concentrations in plasma, buffy coat, and lung tissue.
To elucidate factors contributing to azithromycin's efficacy against macrolide-resistant bacteria.

Main Methods:

Determined macrolide concentrations (azithromycin, clarithromycin, erythromycin) in plasma and buffy coat of normal and sepsis model rats.
Assessed drug transport into lung tissue.
Analyzed leukocyte counts and drug accumulation per leukocyte.

Main Results:

Macrolide levels were higher in the buffy coat than plasma, with increased accumulation per leukocyte in septic rats.
Lung tissue concentrations remained consistent in septic rats compared to normal rats.
Azithromycin exhibited long-term stasis in lung tissue.

Conclusions:

Phagocyte delivery of azithromycin contributes to its efficacy.
Sustained presence (stasis) of azithromycin in lung tissue is a key factor.
These combined pharmacokinetic properties explain clinical success against resistant strains.

Read full analysis

Keywords:

Macrolides antimicrobial resistance disposition sepsis

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