Susceptibility and resistance emergence studies with macrolides

Area of Science:

• Pharmacology
• Microbiology
• Infectious Diseases

Background:

• Oral azithromycin achieves prolonged high concentrations in infected tissues due to its extended elimination half-life and good penetration.
• Concerns exist that prolonged subinhibitory azithromycin levels post-therapy may induce bacterial resistance, unlike other macrolides.

Purpose of the Study:

• To evaluate the potential for azithromycin resistance emergence under prolonged therapeutic concentrations in clinical and preclinical models.
• To reassess macrolide and azithromycin resistance estimations, particularly concerning the influence of carbon dioxide (CO2) incubation.

Main Methods:

• In vitro susceptibility testing of bacterial strains.
• An animal model of tissue infection.
• A clinical study involving pediatric patients.
• Comparative analysis of resistance under varying incubation conditions (including CO2 presence).

Main Results:

• Data from in vitro studies, an animal model, and a pediatric clinical trial suggest prolonged azithromycin tissue concentrations are unlikely to foster resistance in clinical practice.
• In vitro studies indicate that bacterial resistance to macrolides, especially azithromycin, is significantly overestimated when strains are incubated with CO2.

Conclusions:

• Prolonged azithromycin exposure in infected tissues is unlikely to lead to clinical resistance.
• Standard in vitro susceptibility testing may overestimate azithromycin resistance due to neglecting the impact of CO2 incubation.