Ketolides — The Modern Relatives of Macrolides

As with other widely used antibacterials, the abundant use of macrolides for management of ambulant infections has promoted emergence of resistance against them. Ketolides are structurally related to macrolides and were developed to overcome macrolide resistance, while sharing pharmacodynamic and pharmacokinetic characteristics. However, until now, there have been no comprehensive reviews of the comparative pharmacokinetics of macrolides and ketolides.

This article reviews the pharmacokinetic parameters in plasma and relevant tissues of telithromycin, the only approved ketolide, and cethromycin, which is currently in phase III of clinical development. For comparison, the 14-membered macrolides clarithromycin and roxithromycin and the 15-membered azalide azithromycin were chosen as representatives of their class.

While telithromycin achieves higher plasma concentrations than cethromycin, both antimicrobials display comparable elimination half-lives and clearance. Repeated dosing rarely influences the pharmacokinetic parameters of ketolides. Despite substantially higher maximum plasma concentrations and area under the plasma concentration-time curve (AUC) values of telithromycin, the higher antimicrobial activity of cethromycin leads to similar ratios between the AUC from 0 to 24 hours (AUC₂₄) and the minimum inhibitory concentration (MIC) for relevant pathogens, suggesting comparable antimicrobial activity of both antimicrobials in plasma. Although telithromycin and cethromycin show plasma-protein binding of 90%, they have excellent tissue penetration, as indicated by volumes of distribution of about 500 L and high intracellular concentrations. Besides enhancing killing of intracellular pathogens, the high concentrations of macrolides, azalides and ketolides in leukocytes have been associated with increased delivery of the antimicrobial agent to the site of infection.

Although telithromycin has been shown to accumulate in alveolar macrophages and epithelial lining fluid by 380- and 15-fold, respectively (relative to plasma concentrations), its concentration in the interstitium of soft tissues is comparable to the free fraction in plasma. Thus the pharmacokinetics of ketolides may help to explain their good activity against a wide range of respiratory tract infections, although pharmacokinetic/pharmacodynamic calculations based on plasma pharmacokinetics would indicate only minor activity against pathogens except streptococci. In contrast, AUC₂₄/MIC ratios achieved in soft tissue may be considered insufficient to kill extracellular pathogens causing soft tissue infections, except for Streptococcus pyogenes.

Although ketolides and macrolides share relevant pharmacokinetic properties, the pharmacokinetics of both antimicrobial classes are not considered interchangeable. With a volume of distribution similar to that of azithromycin but plasma concentrations and an elimination half-life reflecting those of clarithromycin, the pharmacokinetics of ketolides may be considered ‘intermediate’ between those of macrolides and azalides. Thus the pharmacokinetics of ketolides can be considered similar but not identical to those of macrolides.