Validation of Optimal Ampicillin/Sulbactam Ratio in Dosage Forms Using In-Vitro Dynamic Model

To validate the optimal ampicillin/sulbactam ratio in dosage forms the antimicrobial action kinetics of the combinations against ampicillin-resistant strain of E. coli (MIC = 250 μg/ml) under simulated clinical conditions in an in-yitro dynamic model was studied. The in-yitro dynamic model simulating the drug kinetic profiles described by the two-compartment pharmacokinetic model (serum drug kinetics after intravenous injection) and the one-compartment pharmacokinetic model (drug profiles in serum and tissue fluid after oral and intravenous administration respectively) was used. The profiles realized after receiving of 0.5 g of ampicillin and 0.125, 0.25, 0.5, 1.0 g of sulbactam were reproduced. Changes in the viable count in the dynamic model were estimated microcalorimetrically with BioActivity Monitor LKB 2277-202. The use of the recently developed parameter of antimicrobial effect duration TE (the time from the moment of drug administration till the moment when the bacterial count reaches again its initial level) provided determination of relationship between effect and ampicillin/sulbactam ratios. It is demonstrated that the variation of ampicillin/sulbactam ratio from 4:1 to 1:1 was accompanied by marked enhancement in the antimicrobial effect. Further increase of sulbactam content in the formulation not resulted in more pronounced effect. We conclude that validation of optimal ratio in chemotherapeutic combinations using in-vitro dynamic models is a promising approach to development of modern drug formulations.