title: Pharmacokinetically-based prediction of the effects of antibiotic combinations on resistant Staphylococcus aureus mutants: in vitro model studies with linezolid and rifampicin.
abstract: To explore if combinations of linezolid (L) with rifampicin (R) are able to restrict Staphylococcus aureus resistance, the enrichment of L- and R-resistant mutants was studied in an in vitro dynamic model. L- and R-resistant mutants were enriched in all single drug treatments. In contrast, L-resistant mutants were not enriched and R-resistant mutants were similar to baseline amounts with only minimal regrowth at the end of the combination treatments. These effects appear to be explained by lowering the mutant prevention concentration (MPC) for L+R combinations (MPCL+R) compared to the MPCs of L and R alone (MPCLand MPCR) and thereby the longer times above MPCL+R(73-100% of the dosing interval for L and 42-58% for R) compared to the times above MPCL(0-44%) and MPCR(0%). These findings provide an opportunity to predict the selection of S. aureus resistance in L+R treatments using MPCL+Rs.
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow 119021 , Russia.
authors.forename: Alexander A
authors.identifier: http://orcid.org/0000-0001-7760-2729
authors.initials: AA
authors.lastname: Firsov
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow 119021 , 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 119021 , Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Strukova
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow 119021 , Russia.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow 119021 , Russia.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Dovzhenko
authors.affiliation: a Department of Pharmacokinetics & Pharmacodynamics , Gause Institute of New Antibiotics , Moscow 119021 , 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
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D006801:Humans; D066298:In Vitro Techniques; D000069349:Linezolid / Q000493:pharmacokinetics / Q000494:pharmacology*; D009154:Mutation; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D014018:Tissue Distribution
chemical_list: D000900:Anti-Bacterial Agents; D000069349:Linezolid; D012293:Rifampin
keywords: Antibiotic combination; In vitro model; Linezolid; Rifampicin; Staphylococcus aureus