title: Predicting effects of antibiotic combinations using MICs determined at pharmacokinetically derived concentration ratios: in vitro model studies with linezolid- and rifampicin-exposed Staphylococcus aureus.
abstract: To predict the effects of combined use of antibiotics on their pharmacodynamics, the susceptibility of Staphylococcus aureus to linezolid-rifampicin combinations was tested at concentration ratios equal to the ratios of 24-area under the concentration-time curve (AUC24) simulated in an in vitro dynamic model. The linezolid MICs in combination with rifampicin decreased 8- to 67-fold. The rifampicin MICs were similar with or without linezolid. The enhanced activity of linezolid combined with rifampicin increased the AUC24/MIC ratios and provided more pronounced antibacterial effects compared with single treatments. The areas between the control growth and time-kill curves (ABBCs) determined in combined and single treatments with linezolid were plotted against AUC24/MIC on the same graph (r20.94). These findings suggest that the effects of linezolid-rifampicin combinations can be predicted by AUC24/MICs of linezolid using its MIC determined at pharmacokinetically derived linezolid-to-rifampicin concentration ratios.
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Maria V
authors.identifier: http://orcid.org/0000-0002-7588-1733
authors.initials: MV
authors.lastname: Golikova
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Elena N
authors.identifier: http://orcid.org/0000-0002-5391-1137
authors.initials: EN
authors.lastname: Strukova
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Dovzhenko
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Mikhail B
authors.initials: MB
authors.lastname: Kobrin
authors.affiliation: b Department of Medicine , Mount Auburn Hospital, Harvard Medical School , Cambridge , MA , USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow , Russia.
authors.forename: Alexander A
authors.identifier: http://orcid.org/0000-0001-7760-2729
authors.initials: AA
authors.lastname: Firsov
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D004338:Drug Combinations; D006801:Humans; D000069349:Linezolid / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests / Q000379:methods; D012293:Rifampin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations; D000069349:Linezolid; D012293:Rifampin
keywords: In vitro dynamic model; Linezolid; Pharmacodynamics; Rifampicin; Staphylococcus aureus