Predicting antibiotic combination effects on the selection of resistant Staphylococcus aureus: in vitro model studies with linezolid and gentamicin.
Int J Antimicrob Agents. 2018 Sep 17;:
Authors: Zinner SH, Golikova MV, Strukova EN, Portnoy YA, Firsov AA
To explore if combinations of linezolid with gentamicin are able to restrict Staphylococcus aureus resistance, the enrichment of resistant mutants was studied in an in vitro dynamic model. A clinical isolate S. aureus 10 and its linezolid-resistant mutant selected by passaging on antibiotic-containing media were used in the study. The MIC and the mutant prevention concentration (MPC) of antibiotics in combination were determined at a linezolid-to-gentamicin concentration ratio that corresponds to the ratio of 24-hour areas under the concentration-time curve (AUC24s) actually used in the pharmacokinetic simulations. Five-day treatments of S. aureus 10 supplemented with linezolid-resistant mutants (mutation frequency 10-8) with twice-daily linezolid and once-daily gentamicin, alone and in combination, were simulated at therapeutic and sub-therapeutic AUC24s. Numbers of linezolid-resistant mutants increased at both therapeutic and subtherapeutic AUC24s, whereas gentamicin-resistant mutants were enriched only at the subtherapeutic AUC24 in single drug treatments. Linezolid-gentamicin combinations prevented the enrichment of linezolid-resistant S. aureus and restricted the enrichment of gentamicin-resistant mutants. The pronounced anti-mutant effect of the combinations was attributed to lengthening the time above MPC of both linezolid and gentamicin as their MPCs were lowered. Unlike resistant S. aureus, killing of the total bacterial burden exposed to linezolid-gentamicin combinations was less than in treatments with gentamicin alone, but it was greater than with linezolid alone. These findings suggest that (1) the anti-mutant effects of antibiotic combinations can be predicted by MPC determinations at pharmacokinetically-derived concentration ratios, and (2) a given antibiotic combination may be optimal against resistant but not susceptible subpopulations.
PMID: 30236953 [PubMed - as supplied by publisher]