A. N. Deitchman, R. P. Singh, J. K. Mukker, S. K. Sy, A. Zoehner, H. Derendorf; University of Florida, Gainesville, FL

BACKGROUND: Tigecycline (TIG), a broad spectrum glycylcycline antibiotic and tetracycline analog, was given a black box warning by the US FDA in 2013 for increased risk of mortality vs. comparator therapy, most likely attributable to treatment failure. Recent investigations have shown that metal-ion chelation increases unbound TIG concentrations. A reversal of this effect by a competitive chelating agent may increase efficacy and possibly broaden TIG activity.
METHODS: In vitro minimum inhibitory concentrations (MIC) of TIG against P. aeruginosa were determined by using serial dilution method in Mueller-Hinton broth in various combinations with EDTA, calcium, and tetracycline (in concentrations less than MIC). Static time kill curves for TIG alone and in combination with 4, 8, and 12 mg/L TET were performed for P. aeruginosa.
RESULTS: For P. aeruginosa, a decrease in TIG MIC from 8 to 0.0625-0.125 mg/L was observed by the addition of EDTA. This enhancement in activity is reversed by the addition of calcium, increasing the MIC to >32 mg/L. The addition of TET in increasing concentrations showed a concentration-dependent improvement in activity with a 2- to 8-fold decrease in MIC. The addition of calcium to TIG-TET combinations reversed this effect. Kill curve data to date has shown enhanced effect of TIG against P. aeruginosa in the presence of TET.
CONCLUSION: TIG-TET synergy against P. aeruginosa has been observed at clinically attainable concentrations. This novel synergism of two compounds of similar structure is likely resultant of competition for calcium chelation. Subsequent investigations have the potential to lead to increasing TIG’s activity at lower doses when given in combination with TET.