Judicious use of antibiotics to minimize emerging resistance: The macrolide clarithromycin as a case study

Infections remain a major cause of death worldwide and antimicrobial resistance is increasing. With fewer new antimicrobial agents in development it is imperative for available antibiotics to last by observing key points: judicious use, appropriate doses and optimizing regimen compliance in order to reduce the risk of increasing resistance. This review discusses these issues, using treatment of the respiratory tract pathogen Streptococcus pneumoniae with the macrolide clarithromycin as a case study. Clarithromycin is active against common respiratory pathogens achieving high tissue, fluid and serum levels, and has a relatively short half-life. These characteristics influence the risk of developing resistance when compared with erythromycin or azithromycin. High local drug concentrations further reduce the risk of therapeutic failure. Long half-lives associated with a long tail in the curve of minimum inhibitory concentration (MIC) over time may increase the risk of emerging resistant strains. Azithromycin has the longest biological half-life among macrolides and was found to be statistically more likely than clarithromycin or erythromycin to select for organisms with higher MIC values. Poor adherence to antibiotic regimens may accelerate the development of resistance. Compliance is enhanced by convenient dosing regimens, for example with extended-release formulations. The ideal antibiotic regimen should achieve maximal-eradication MIC while minimizing the total time with sub-MICs present in the treated population, and have mutant prevention concentration values within clinically achievable and sustainable drug concentrations.