title: In vitro resistance studies with bacteria that exhibit low mutation frequencies: prediction of "antimutant" linezolid concentrations using a mixed inoculum containing both susceptible and resistant Staphylococcus aureus.
abstract: Bacterial resistance studies using in vitro dynamic models are highly dependent on the starting inoculum that might or might not contain spontaneously resistant mutants (RMs). To delineate concentration-resistance relationships with linezolid-exposed Staphylococcus aureus, a mixed inoculum containing both susceptible cells and RMs was used. An RM selected after the 9th passage of the parent strain (MIC, 2 μg/ml) on antibiotic-containing media (RM9; MIC, 8 μg/ml) was chosen for the pharmacodynamic studies, because the mutant prevention concentration (MPC) of linezolid against the parent strain in the presence of RM9 at 10(2) (but not at 10(4)) CFU/ml did not differ from the MPC value determined in the absence of the RMs. Five-day treatments with twice-daily linezolid doses were simulated at concentrations either between the MIC and MPC or above the MPC. S. aureus RMs (resistant to 2× and 4×MIC but not 8× and 16×MIC) were enriched at ratios of the 24-h area under the concentration-time curve (AUC24) to the MIC that provide linezolid concentrations between the MIC and MPC for 100% (AUC24/MIC, 60 h) and 86% (AUC24/MIC, 120 h) of the dosing interval. No such enrichment occurred when linezolid concentrations were above the MIC and below the MPC for a shorter time (37% of the dosing interval; AUC24/MIC, 240 h) or when concentrations were consistently above the MPC (AUC24/MIC, 480 h). These findings obtained using linezolid-susceptible staphylococci supplemented with RMs support the mutant selection window hypothesis. This method provides an option to delineate antibiotic concentration-resistance relationships with bacteria that exhibit low mutation frequencies.
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia firsov@dol.ru.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Golikova
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Strukova
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.affiliation: Institute of Antimicrobial Chemotherapy, Smolensk State Medical Academy, Smolensk, Russia.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Romanov
authors.affiliation: Institute of Antimicrobial Chemotherapy, Smolensk State Medical Academy, Smolensk, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Edelstein
authors.affiliation: Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D059645:Mutation Rate; D023303:Oxazolidinones / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D000069349:Linezolid