Pharmacological considerations in the emergence of resistance

Resistance to macrolides in vitro is increasingly being reported. However, there has been no corresponding increase in clinical failures noted. Lack of clinical failures due to resistance is most likely the result of the high intracellular concentrations that these drugs achieve in phagocytes. In the case of clarithromycin, concentrations in both monocytes and granulocytes fluctuate between peaks of approximately 22-25 mg/l and troughs of approximately 5 mg/l during a standard dosing interval. In contrast, azithromycin attains concentrations of over 60 mg/l in granulocytes and at least 100 mg/l in monocytes. After 7 days, azithromycin concentrations of >32 mg/l are still observed. These data also imply that against pathogens with increasing minimum inhibitory concentrations (MICs), macrolides with relatively lower or less sustained intracellular concentrations will become ineffective clinically much sooner than compounds, such as azithromycin, that concentrate to a high degree and are retained in white blood cells for prolonged periods.