Lack of emergence of significant resistance in vitro and in vivo to the new azalide antibiotic azithromycin

In vitro experiments were performed in which 6 to 12 strains ofStaphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae andEnterobacteriaceae were passaged nine times in sub-lethal concentrations of azithromycin or control antibiotics.Streptococcus pyogenes andStaphylococcus aureus quickly became resistant to rifampin as the MIC90 increased from 0.1 to > 50 µg/ml for both species. The MIC90 of azithromycin, erythromycin, amoxicillin and cefaclor increased by three dilutions forStaphylococcus aureus. The MIC values of azithromycin forStreptococcus pyogenes, Haemophilus influenzae andEnterobacteriaceae strains did not change significantly. However, forHaemophilus influenzae and theEnterobacteriaceae strains, the MIC values of erythromycin and oral cephalosporins increased four-fold. In the in vivo experiments, mice infected withStaphylococcus aureus orEscherichia coli contaminated sutures were administered azithromycin for three days, and on day 6 viable bacterial cells were recovered from the infection site. The sustained tissue concentrations of azithromycin indicated that the organisms would have been continuously exposed to azithromycin at the site of infection. Colonies isolated from azithromycin-treated and non-treated mice were cultured and their susceptibility to azithromycin compared. The azithromycin MIC values forStaphylococcus aureus cultures from treated and non-treated animals were identical. The azithromycin MICs forEscherichia coli recovered from treated animals were on average, less than one dilution higher than for control cultures. Emergence of significant resistance to azithromycin in the laboratory was not observed with the pathogens tested.