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Preferential concentration of azithromycin in an infected mouse thigh model
J A Retsema1, J M Bergeron, D Girard
1Central Research Division, Pfizer Inc, Groton, CT 06340.
Abstract:
The possibility of augmentation of azithromycin delivery to infection loci was evaluated by the use of Staphylococcus aureus thigh infection models with CD-1 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 saline-injected thighs, from 24 to > or = 72 h after infection. Azithromycin concentrations were enhanced significantly (P < or = 0.02) 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 < or = 24 h. The data indicate that delivery of biologically available azithromycin to infected tissues is enhanced by cellular inflammatory processes.
Insights
Azithromycin delivery to infection sites is enhanced by inflammation, particularly by polymorphonuclear leucocytes. This increased concentration in infected tissues leads to better bacterial clearance in Staphylococcus aureus models.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Azithromycin is a macrolide antibiotic used to treat bacterial infections.
- Understanding drug delivery to infection sites is crucial for optimizing antimicrobial therapy.
- Inflammatory processes can influence the pharmacokinetic properties of antibiotics.
Purpose of the Study:
- To evaluate the augmentation of azithromycin delivery to infection loci.
- To investigate the role of inflammation and cellular infiltration in azithromycin concentration at infection sites.
- To compare azithromycin's tissue distribution with other macrolides in an infection model.
Main Methods:
- Utilized Staphylococcus aureus thigh infection models in CD-1 mice.
- Assessed bacterial growth, edema formation (gravimetrically), and polymorphonuclear leucocyte infiltration.
- Quantified azithromycin concentrations in infected and non-infected tissues at various time points post-infection and dosing.
Main Results:
- Azithromycin concentrations were significantly enhanced in infected thigh tissues compared to non-infected tissues.
- Enhanced azithromycin levels correlated with edema and bacterial load, particularly between 24-72 hours.
- Delayed azithromycin administration during more severe inflammation resulted in even greater preferential concentration.
Conclusions:
- Cellular inflammatory processes, specifically polymorphonuclear leucocyte infiltration, enhance the delivery of biologically available azithromycin to infected tissues.
- The concentration of azithromycin in infected tissues was sufficient to reduce bacterial counts (cfu).
- Other macrolides like erythromycin, roxithromycin, and clarithromycin did not show preferential concentration in infected tissues under similar conditions.
