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Clinical relevance of intracellular and extracellular concentrations of macrolides

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Summary

The serum levels of the three macrolides—roxithromycin, clarithromycin and azithromycin—vary considerably. The prediction of the antibacterial effect against extracellular pathogens is based on circulating concentrations of free drug, peak and trough levels, the rate of killing, and the presence of a post-antibiotic effect. Intracellular activity depends on the distribution of the antibiotic and the localization of the bacteria, and is variable. Roxithromycin uptake is greater than that of erythromycin. The intracellular half-life may be long for some compounds (azithromycin>roxithromycin). The intracellular distribution is bimodal, both in the lysosomes and the cytoplasm, but the mechanisms of uptake have not yet been established. At low pH, accumulation is low and macrolides are less active in an acidic medium. Intracellular concentrations cannot readily be predicted on the basis of extracellular levels. Different models have shown that the greater the intracellular concentration, the better the clinical effect. In addition, the transport of macrolides by cells into the infected focus may play an important role in the therapeutic outcome. These factors influence the clinical indications for macrolides, their dosing regimens and breakpoints. In future, macrolides will be developed that are more selective for intracellular infections, while others, which will achieve significant serum levels, will be useful for a broader range of diseases. However, new compounds should be evaluated in different models of infection before clinical studies are instituted. The analysis of failures remains the most important approach in defining concentration/effect relationships.

Zusammenfassung

Die Serumkonzentrationen der Makrolide Roxithromycin, Clarithromycin und Azithromycin variieren beträchtlich. Die Voraussage der antibiotischen Wirksamkeit einer ungebundenen Droge basiert auf dem Spitzen- und Talspiegel, der Abtötungsrate und eines vorhandenen postantibiotischen Effekts. Die intrazelluläre Aktivität einer antimikrobiellen Substanz hängt von dem variablen Verteilungsvolumen des Antibiotikums und der Lokalisation der Bakterien ab. Die Roxithromycinaufnahme ist größer als die von Erythromycin. Die intrazelluläre Halbwertzeit kann für manche Substanzen überdurchschnittlich lang sein (Azithromycin>Roxithromycin). Die intrazelluläre Verteilung ist außerdem in Lysosomen und Zytoplasma verschieden, jedoch ist der Mechanismus der Aufnahme noch nicht geklärt. Bei niedrigem pH-Wert ist die Anreicherung der Makrolide gering und im sauren Medium von reduzierter Aktivität. Eine zuverlässige Korrelation zu extrazellulären Konzentrationen besteht nicht. Der antibiotische Effekt ist jedoch von der Höhe der intrazellulären Konzentration abhängig. Zudem mag der zellgebundene Makrolidtransport zum Fokus eine erhebliche Rolle für das Therapieergebnis spielen. Die genannten Faktoren beeinflussen die Indikationen der Makroliden, ihre Dosierung und die „breakpoints” der Serumkonzentrationen. In der Zukunft werden möglicherweise Makrolide entwickelt werden, die eine größere Selektivität im Hinblick auf intrazelluläre Infektionen aufweisen, während andere, die signifikante Serumspiegel erreichen, für ein breiteres Spektrum von Infektionen brauchbar sind. Dies müßte jedoch in verschiedenen Infektionsmodellen ausgewertet werden bevor klinische Studien veranlaßt werden. Die Analyse der Therapieversager bleibt der wichtigste Zugang zur Definition der Konzentrations-Wirkungsbeziehung.

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Carbon, C. Clinical relevance of intracellular and extracellular concentrations of macrolides. Infection 23 (Suppl 1), S10–S14 (1995). https://doi.org/10.1007/BF02464953

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