Advanced-generation macrolides: tissue-directed antibiotics

Area of Science:

• Pharmacology
• Microbiology
• Infectious Diseases

Background:

• Erythromycin was the first clinically used macrolide antibiotic.
• Advanced-generation macrolides include azithromycin, clarithromycin, dirithromycin, and roxithromycin.
• These newer macrolides exhibit distinct pharmacokinetic properties compared to erythromycin.

Purpose of the Study:

• To compare the pharmacokinetic and pharmacodynamic properties of advanced-generation macrolides, particularly azithromycin.
• To highlight the clinical utility of azithromycin's tissue-specific concentrations.
• To emphasize the need for new models to explain the efficacy of intracellularly concentrated antibiotics.

Main Methods:

• Review of pharmacokinetic data for azithromycin and other advanced-generation macrolides.
• Analysis of antimicrobial spectrum, including Gram-positive, atypical, anaerobic, and Gram-negative pathogens.
• Discussion of azithromycin's concentration within polymorphonuclear leukocytes and at infection sites.

Main Results:

• Advanced-generation macrolides demonstrate low serum and high tissue concentrations, with azithromycin having an extended tissue elimination half-life.
• Azithromycin allows for a 3-day once-daily dosing regimen for respiratory tract infections, shorter than other macrolides.
• These macrolides are concentrated in leukocytes, leading to high intracellular pathogen exposure.
• Azithromycin and clarithromycin's metabolite show activity against community-acquired Gram-negative organisms like Haemophilus influenzae.

Conclusions:

• Azithromycin's unique pharmacokinetic profile, characterized by high and prolonged tissue concentrations, supports its clinical efficacy.
• Traditional pharmacodynamic models are insufficient for explaining the effectiveness of antibiotics achieving high intracellular concentrations.
• Future research should focus on tissue pharmacokinetic and pharmacodynamic concepts for azithromycin.