Ubrolexin® - About synergy

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Synergy: where the final outcome of a system is greater than the sum of its parts

 

1 + 1 = 3

 

Synergism can be qualitatively defined as a positive interaction achieved when the combined effect of drugs examined is significantly greater than the expected results achieved when the individual drugs are used separately.

 

In Ubrolexin®, the effect of cefalexin is enhanced by kanamycin and vice versa.

  • Mechanism of synergy in Ubrolexin®

    One of the most commonly accepted mechanisms of antibacterial synergism is the enhanced intracellular uptake of one antimicrobial which is facilitated by the cell-wall activity of the other.

     

    In Ubrolexin®, Cefalexin is the cell-wall active agent which alters the permeability of the bacteria. Cefalexin facilitates the access of Kanamycin to its intracellular target, the 30s ribosomal subunit, resulting in bactericidal synergistic activity of the combination.

     

    Through their complementary modes of action, Cefalexin and Kanamycin are combined in Ubrolexin® in such a way (the fixed ratio of 1.5 : 1 and the respective antibiotic concentrations) that synergism from their specific properties can be fully exploited.

     

    Hence, the Ubrolexin® combination is designed to achieve a mutual enhancement of their respective antimicrobial activity in order to offer the most effective killing rate of bacteria.

  • How to measure synergy?

    A kill kinetic study was carried out, investigating the rate of bacterial killing achieved by the Cefalexin : Kanamycin combination at a fixed ratio of 1.5 : 1 (the initial ratio of antibiotics in the intramammary injector).

     

    The in vitro bactericidal activity of Cefalexin and Kanamycin, alone and in combination, was assessed against Streptococcus uberis, Staphylococcus aureus and Escherichia coli strains isolated from field cases of bovine mastitis.

     

    In this study, a wide range of Cefalexin : Kanamycin concentrations were tested, all at a ratio of 1.5 : 1, the initial ratio value in the Ubrolexin® injector. The tested range of concentrations includes those likely to be achieved in the udder after administration of Ubrolexin®.

     

    Comparisons of the time kill curves of Cefalexin, Kanamycin and combination thereof at the lowest antibiotic concentrations showing additive or synergistic effect against Comparisons of the time kill curves of Cefalexin, Kanamycin and combination thereof at the lowest antibiotic concentrations showing additive or synergistic effect against Staphylococcus aureus, Streptococcus uberis and Escherichia coli:

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    The kill kinetics experiment with a fixed cefalexin : kanamycin ratio demonstrated the occurrence of synergistic interactions between Cefalexin and Kanamycin, resulting in a faster and enhanced bactericidal activity against major mastitis pathogens, as compared to the single compounds alone.

     

    Major pathogens are killed in vitro in less than 9 hours.

     

    Synergistic interactions between Cefalexin and Kanamycin were also observed in milk

  • Killing curves to detect synergy

    In contrast to other techniques based on Minimum Inhibitory Concentrations (MICs), which provides only inhibitory data, the killing curve method of synergy testing assesses the bactericidal activity of the combination being tested.

     

    The killing curve technique offers the advantage of a dynamic picture of the bactericidal activity and interaction over time: the time-kill methodology is based on serial bacterial colony count determination (expressed in colony-forming units / CFU per ml) at periodic intervals, until up to 12 or 24 hours. A killing curve or killing rate can then be plotted from the numbers of survivors after administration of a given drug.

     

    Each organism is tested against each antimicrobial agent alone and in combination within a predefined range of concentration dilutions around the MIC. When the colony counts have been determined, they are plotted on semi logarithmic paper (using the abscissa for time and the ordinate (logarithmic scale for the survivor colony counts).

     

    Synergy is usually defined as a ≥ 100-fold increase in killing (at least 2-log10 decrease in colony count) with the combination, in comparison with the most active single agent alone.

     

    Additivity or indifference is defined as a < 100-fold change in colony count by the combination compared with that by the most active single agent.