Predicting the antistaphylococcal effects of daptomycin–rifampicin combinations in an in vitro dynamic model

• Published in: Journal of antibiotics Vol. 73; no. 2; pp. 101 - 107
• Main Authors: Golikova, Maria V., Strukova, Elena N., Portnoy, Yury A., Zinner, Stephen H., Firsov, Alexander A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 631/154/436/1729; 631/154/436/2388; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibiotics; Area Under Curve; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Daptomycin - administration & dosage; Daptomycin - pharmacokinetics; Daptomycin - pharmacology; Drug Therapy, Combination; Economic models; Life Sciences; Medicinal Chemistry; Microbial Sensitivity Tests; Microbiology; Organic Chemistry; Rifampin - administration & dosage; Rifampin - pharmacokinetics; Rifampin - pharmacology; Staphylococcus aureus - drug effects
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-019-0249-x

To predict the effects of combined use of antibiotics on their pharmacodynamics, the susceptibility of Staphylococcus aureus to daptomycin–rifampicin combinations was tested at concentration ratios equal to the ratios of daptomycin and rifampicin 24-h areas under the concentration-time curve (AUC 24 s) simulated in an in vitro dynamic model. In combination with rifampicin, daptomycin MICs decreased 2- to 31-fold, whereas rifampicin MICs were similar with or without daptomycin. The enhanced susceptibility of S. aureus to daptomycin combined with rifampicin resulted in both an increase of the actual AUC 24 /MIC ratios and also more pronounced antibacterial effects compared with single treatments. The areas between the control growth and time-kill curves (ABBCs) determined in combined and single daptomycin treatments were plotted against AUC 24 /MIC on the same graph ( r 2 0.90). These findings suggest that the effects of daptomycin–rifampicin combinations can be predicted by AUC 24 /MICs of daptomycin using its MIC determined at pharmacokinetically derived daptomycin-to-rifampicin concentration ratios.