MPC-Based Prediction of Anti-Mutant Effectiveness of Antibiotic Combinations: In Vitro Model Study with Daptomycin and Gentamicin against <i>Staphylococcus aureus</i>

• Main Authors: Maria V. Golikova (Author), Elena N. Strukova (Author), Yury A. Portnoy (Author), Stephen H. Zinner (Author), Alexander A. Firsov (Author)
• Format: Book
• Published: MDPI AG, 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics10101148; 2079-6382
• Keywords: daptomycin-gentamicin combination; in vitro model; anti-mutant effect; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 10, Iss 10, p 1148 (2021)

To explore whether combined treatments with daptomycin and gentamicin can prevent the development of <i>Staphylococcus aureus</i> resistance, and whether the possible restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicin-resistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model. The MPCs of the antibiotics in the combination were determined at concentration ratios equal to the ratios of 24 h areas, under the concentration-time curve (AUCs) of the antibiotics, as simulated in pharmacodynamic experiments. The MPCs of both daptomycin and gentamicin decreased in the presence of each other; this led to an increase in the time when antibiotic concentrations were above the MPC (<i>T</i>_>MPC). The increases in <i>T</i>_>MPCs were concurrent with increases of the anti-mutant effects of the combined antibiotics. When anti-mutant effects of the antibiotics in single and combined treatments were plotted against the <i>T</i>_>MPCs, significant sigmoid relationships were obtained. These findings suggest that (1) daptomycin-gentamicin combinations prevent the development of <i>S. aureus</i> resistance to each antibiotic; (2) the anti-mutant effects of antibiotic combinations can be predicted using MPCs determined at pharmacokinetic-based antibiotic concentration ratios; (3) <i>T</i>_>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations.