The generation of large changes in the crystal frequency is a highly sought-after goal in designing a successful thickness-shear mode (TSM) acoustic wave sensor application. We examined the potential for modulating the mass loading and viscoelastic properties of a swellable polymeric coating to achieve this goal. Using a 10 MHz AT-cut crystal with an immobilized coating of a styrene-divinylbenzene copolymer, a high molecular weight target analyte with complementary ionic and molecular binding properties was selected. Injection of the antibiotic cefoperazone in a sodium acetate buffer generated exceptionally large changes in frequency, in the range 500 - 5000 Hz. The rate of change in frequency is proportional to the analytical concentration. A multi-step regeneration protocol allows the coating to be reused multiple times. These results suggest that TSM sensor sensitivities can be significantly enhanced for selected analytes by the judicious selection of an appropriate swellable polymer coating.