Advanced-generation macrolides: tissue-directed antibiotics.

The azalide antibiotic azithromycin and the newer macrolides, such as clarithromycin, dirithromycin and roxithromycin, can be regarded as 'advanced-generation' macrolides compared with erythromycin, the first macrolide used clinically as an antibiotic. Their pharmacokinetics are characterized by a combination of low serum concentrations, high tissue concentrations and, in the case of azithromycin, an extended tissue elimination half-life. Azithromycin is particularly noted for high and prolonged concentrations at the site of infection. This allows once-daily dosing for 3 days in the treatment of respiratory tract infections, in contrast to longer dosage periods required for erythromycin, clarithromycin, roxithromycin and agents belonging to other classes of antibiotics. The spectrum of activity of the advanced-generation macrolides comprises Gram-positive, atypical and upper respiratory anaerobic pathogens. Azithromycin and the active metabolite of clarithromycin also demonstrate activity against community-acquired Gram-negative organisms, such as Haemophilus influenzae. Advanced-generation macrolides, and in particular azithromycin, are highly concentrated within polymorphonuclear leucocytes, which gravitate by chemotactic mechanisms to sites of infection. Following phagocytosis of the pathogens at the infection site, they are exposed to very high, and sometimes cidal, intracellular concentrations of antibacterial agent. Pharmacodynamic models and susceptibility breakpoints derived from studies with other classes of drugs, such as the beta-lactams and aminoglycosides, do not adequately explain the clinical utility of antibacterial agents that achieve high intracellular concentrations. In the case of azithromycin, attention should focus on tissue pharmacokinetic and pharmacodynamic concepts.