Ahmed H Salem1, Walid F Elkhatib, Ayman M Noreddin. 1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA. sale0074@umn.edu
Abstract
OBJECTIVES: A combination of vancomycin and rifampicin (rifampin) is commonly used to treat staphylococcal infections but its efficacy against methicillin-resistant Staphylococcus aureus (MRSA) biofilm is controversial. The objective of this study was to use a recently developed quantitative methodology to characterise the killing effect of vancomycin and rifampin combination against MRSA biofilm. METHODS: MRSA biofilm was exposed to escalating concentrations of vancomycin and rifampin and the viability of the biofilm-ensconced bacteria was evaluated. ADAPT II was used to model the concentration-effect relationship and determine the optimal sampling concentrations. Combination experiments were then conducted and the observations were compared with a simulated response surface representing null interaction. Finally, the pharmacodynamic interaction index (PDI) was computed as the ratio of the volumes under the observed and simulated surfaces. KEY FINDINGS: In the combination experiments, all observations showed an inferior antibacterial effect to what is expected under null interaction assumption and the PDI was estimated to be 3.36 (95% CI, 3.25 to 3.46). CONCLUSIONS: The results of the study demonstrate in-vitro antagonism between vancomycin and rifampin against MRSA biofilm. The quantitative approach employed to quantify the antibacterial effect of the combination provides a scientific rationale for further in-vivo investigations that should allow a better understanding of the therapeutic potential of this combination in biofilm-associated MRSA infections.
OBJECTIVES: A combination of vancomycin and rifampicin (rifampin) is commonly used to treat staphylococcal infections but its efficacy against methicillin-resistant Staphylococcus aureus (MRSA) biofilm is controversial. The objective of this study was to use a recently developed quantitative methodology to characterise the killing effect of vancomycin and rifampin combination against MRSA biofilm. METHODS: MRSA biofilm was exposed to escalating concentrations of vancomycin and rifampin and the viability of the biofilm-ensconced bacteria was evaluated. ADAPT II was used to model the concentration-effect relationship and determine the optimal sampling concentrations. Combination experiments were then conducted and the observations were compared with a simulated response surface representing null interaction. Finally, the pharmacodynamic interaction index (PDI) was computed as the ratio of the volumes under the observed and simulated surfaces. KEY FINDINGS: In the combination experiments, all observations showed an inferior antibacterial effect to what is expected under null interaction assumption and the PDI was estimated to be 3.36 (95% CI, 3.25 to 3.46). CONCLUSIONS: The results of the study demonstrate in-vitro antagonism between vancomycin and rifampin against MRSA biofilm. The quantitative approach employed to quantify the antibacterial effect of the combination provides a scientific rationale for further in-vivo investigations that should allow a better understanding of the therapeutic potential of this combination in biofilm-associated MRSA infections.
Authors: Kushal Vanamala; Katyayani Tatiparti; Ketki Bhise; Samaresh Sau; Marc H Scheetz; Michael J Rybak; David Andes; Arun K Iyer Journal: Drug Discov Today Date: 2020-10-20 Impact factor: 7.851