Active Ingredients: Azithromycin
However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors.
However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern.
In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.
In addition to time-dependent bacteriostatic or bactericidal activity, which it shares with most other macrolides 3, azithromycin can also show concentration-dependent bactericidal activity against some organisms 5 and displays an important postantibiotic effect 6.
In this context, the most prominent feature of azithromycin is its ability to concentrate in intracellular compartments, mainly in fibroblasts, phagocytic cells, and other white blood cells WBC 8. Because of the drug's dibasic molecular structure, which is unique among the otherwise monobasic macrolide compounds, azithromycin is confined within the acidic lysosomes of WBC due to an ion-trapping mechanism.
Subsequently, it is released only very slowly from intracellular compartments 10. This is believed to account for the sustained drug concentrations in tissues which are reported to persist long after the end of therapy 11, 12, as reflected by a long and biphasic elimination half-life of up to 5 days 7.
On the other hand, concern has been expressed about the presence of subinhibitory azithromycin concentrations in tissue after the end of therapy 13, since they might trigger the emergence of bacterial resistance 14.
It is important to mention that most bacterial infections take place in the interstitium.
Hence, it is the drug concentration in this very compartment. So far, azithromycin concentrations have been measured in WBC and different tissue-specific phagocytes 17 — 19. Azithromycin concentrations have also been determined in body fluids such as bronchoalveolar washing, gastric juice, sputum, and peritoneal dialysis fluid 17 — 19, 21, 24, 25.
However, despite interstitial skin and soft tissue infections constituting one of the drug's main therapeutic targets, data on azithromycin pharmacokinetics in the extracellular space of human soft tissues, such as muscle and subcutaneous adipose tissue, are still missing.
Therefore, the present study was designed to measure the free, microbiologically active concentration-time profile of azithromycin in extracellular space fluid of muscle and subcutaneous adipose tissue of healthy volunteers, during and up to 7 days after the end of active treatment.