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

Maria V Golikova,Stephen H Zinner,Elena N Strukova,Yury A Portnoy,Alexander A Firsov

doi:10.3390/antibiotics10101148

Abstract

To explore whether combined treatments with daptomycin and gentamicin can prevent the development of Staphylococcus aureus 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 (T>MPC). The increases in T>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 T>MPCs, significant sigmoid relationships were obtained. These findings suggest that (1) daptomycin–gentamicin combinations prevent the development of S. aureus 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) T>MPC is a reliable predictor of the anti-mutant efficacy of antibiotic combinations.

Highlights

Emerging trends in antimicrobial resistance (AMR) presuppose the need to search for effective tools to improve treatment outcomes
The few extant in vivo studies have not shown that daptomycin–gentamicin combination is superior to daptomycin alone as applied to the suppression of resistance [9,10]; in one of the studied S. aureus strains, the development of daptomycin resistance was restricted in the presence of gentamicin [10]
To explore whether combined treatments with daptomycin and gentamicin can prevent the enrichment of S. aureus mutants resistant to both drugs, and if such restriction is associated with changes in antibiotic mutant prevention concentrations (MPCs), the enrichment of daptomycin- and gentamicinresistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model

Summary

Introduction

Emerging trends in antimicrobial resistance (AMR) presuppose the need to search for effective tools to improve treatment outcomes. In other studies [14,15], only the prevention of gentamicin resistance in the presence of daptomycin was detected, while resistance to daptomycin did not occur in mono- or combined treatments These sparse data do not allow conclusions about daptomycin– gentamicin interactions in relation to anti-mutant effects. To explore whether combined treatments with daptomycin and gentamicin can prevent the enrichment of S. aureus mutants resistant to both drugs, and if such restriction is associated with changes in antibiotic MPCs, the enrichment of daptomycin- and gentamicinresistant mutants was studied by simulating 5-day single and combined treatments in an in vitro dynamic model. As referenced above [16], the MPCs of one antibiotic, in the presence of the other, were determined at a pharmacokinetic-based daptomycin-to-gentamicin concentration ratio, which was equal to the ratio of the AUC of daptomycin to the AUC of gentamicin in pharmacokinetic simulations of the combined treatments

MPCs of Daptomycin and Gentamicin Alone and in Combination

Materials and Methods

MPC Determinations

Antibiotic Dosing Regimens and Simulated Pharmacokinetic Profiles

In Vitro Dynamic Model

Conclusions