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

Abstract

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 ofStaphylococcus aureus and Escherichia coliby 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) andE. 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.

A Proposal of a Pharmacokinetic/pharmacodynamic (PK/PD) Index Map for Selecting an Optimal PK/PD Index from Conventional Indices (AUC/MIC, Cmax/MIC, and TAM) for Antibiotics

“…16) Generally this inconsistency has been attributed to factors like post antibiotic effect (PAE) or sub-MIC effect (SME). 17) However, the PK/PD index map would suggest that AUC/MIC is a good index for a time-dependent drug such as azithromycin, without employing additional factors. These observations suggest that the PK/PD index map can be a better predictor of the antibacterial effect than the conventional classification.…”

Molecular Investigation of the Postantibiotic Effects of Clarithromycin and Erythromycin on Staphylococcus aureus Cells

“…Some investigators have simply diluted treated cells by a factor sufficient to reduce the drug to a subinhibitory concentration, and they have then measured the resumption of growth by cell viability measurements (11,16,17,20,25,29). Other studies involved removal of antibiotics from the medium by centrifugation or filtration of the cells with washing to remove the drug (10,18,21). In these cases the cells are normally resuspended at the same density as before the drug removal.…”

“…A number of different microorganisms have been shown to exhibit a PAE, including Haemophilus influenzae (20), mycobacteria (18), and pneumococci (26). Studies of the macrolide PAE on Staphylococcus aureus cells have been particularly numerous (10,11,16,17,25,29). In addition to the macrolides, a PAE has been demonstrated in S. aureus with other antibiotics, including tobramycin (9), ampicillin (11), and isepamicin (10).…”

“…Studies of the macrolide PAE on Staphylococcus aureus cells have been particularly numerous (10,11,16,17,25,29). In addition to the macrolides, a PAE has been demonstrated in S. aureus with other antibiotics, including tobramycin (9), ampicillin (11), and isepamicin (10). Although many studies have investigated the PAE, only a few have examined the molecular events occurring during the persisting inhibition (2,15,32).…”

“…Recovery from both inhibitory activities is presumably required for cells to resume growth after antibiotic removal. A PAE has been demonstrated in S. aureus cells with the macrolide antibiotics erythromycin (11,16,17,20,29), clarithromycin (16), azithromycin (10,16), and roxithromycin (16,17). The PAE demonstrated by cells after macrolide removal suggests that one or both of these processes is limiting for recovery from drug treatment.…”