Preferential concentration of azithromycin in an infected mouse thigh model

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Abstract
The possibility of augmentation of azithromycin delivery to infection loci was evaluated by the use of Staphylococcus aureus thigh infection models with CD-I mice. The intramuscular infections that developed were characterized by rapid growth of bacteria and induction of a localized oedema that was assessed gravimetrically. Microscopic examination of infected thighs showed massive infiltration of polymorphonuclear leucocytes (viable and degranulated), when compared to salineinjected thighs, from 24 to ≥ 72 h after infection. Azithromycin concentrations were enhanced significantly ( P ≤ O.02) in infected thigh tissues compared with contralateral non-infected tissues, and correlated with oedema from 24–72 h after challenge and dosing. The azithromycin levels in infected tissue after a 5 mg/kg dose were sufficient to cause a significant reduction in the number of cfu. If azithromycin administration was delayed until inflammation was more severe, the result was an even greater preferential concentration of azithromycin into the infected thigh. Preferential concentration of azithromycin was not observed when extensive oedema was produced by injection of histamine. However, this oedema was not associated with a significant influx of polymorphonuclear leucocytes. In comparative studies, macrolide antibiotics known to be concentrated in phagocytes, such as erythromycin, roxithromycin, and clarithromycin, were not concentrated preferentially in infected tissues under the experimental conditions used; tissue levels were above or at the in-vitro MIC level for ≤ 24 h. The data indicate that delivery of biologically available azithromycin to infected tissues is enhanced by cellular inflammatory processes.

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