Postantibiotic and Sub-MIC Effects of Azithromycin and Isepamicin against Staphylococcus aureus and Escherichia coli

Investigations of pharmacodynamic parameters (postantibiotic effect [PAE], sub-MIC effects [SMEs], etc.) have been progressively employed for the design of dosing schedules of antimicrobial agents. However, there are fewer in vivo than in vitro data, probably because of the simplicity of the in vitro procedures. In this study, we have investigated the in vitro PAE, SME, and previously treated (postantibiotic [PA]) SME (1/2 MIC, 1/4 MIC and 1/8 MIC) of azithromycin and isepamicin against standard strains of Staphylococcus aureus and Escherichia coli by using centrifugation to remove the antibiotics. In addition, the in vivo PAE and SME have been studied with the thigh infection model in neutropenic mice. Finally, in vivo killing curves with two dosing schedules were determined to examine whether the PAE can cover the time that antimicrobial agents are below the MIC. The two antimicrobial agents induced moderate-to-high in vitro PAEs, SMEs, and PA SMEs against S. aureus (>8 h) and E. coli (3.38 to >7.64 h). The in vivo PAEs were also high (from 3.0 to 3.6 h), despite the fact that isepamicin had lower times above the MIC in serum. Only azithromycin showed a high in vivo SME against the two strains (1.22 and 1.75 h), which indicated that the in vivo PAEs were possibly overestimated. In the killing kinetics, no great differences (<0.5 log10) were observed between the schedule that took the PAE into account and the continuous administration of doses. These results are comparable with those of other authors and suggest that these antimicrobial agents could be administered at longer intervals without losing effectiveness.