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Therap.<\/jats:italic><jats:bold>34<\/jats:bold>, 487\u2013493.<\/jats:p><jats:p>Beta\u2010lactam antimicrobials, commonly used in both veterinary and human medicine, generally present short biologic half\u2010lives, whereas their activity is enhanced as pathogen exposure is prolonged. These properties necessitate multiple\u2010dose regimens of standard dosage forms, thereby hampering pet owner adherence, frequently resulting in therapeutic failure. This study presents a novel controlled\u2010release gastroretentive oral drug delivery system for beta\u2010lactams with which single\u2010dose administration provides an effective antimicrobial course, optimizing pharmacokinetic (PK)\u2013pharmacodynamic (PD) profiles, minimizing adverse effects and emergence of antimicrobial resistance and facilitating adherence. Our prototype sustained\u2010delivery swelling\u2010tablet (SDST), based on a degradable hydrophilic polymeric matrix, was designed to enable continuous input of these drugs to their absorption sites over several days. Several SDST formulations of the beta\u2010lactam amoxicillin were evaluated in <jats:italic>in vitro<\/jats:italic> dissolution studies. Two formulations were selected for further <jats:italic>in vivo<\/jats:italic> canine studies, for determination of gastric retention and PK\u2013PD profiling. Prolonged gastric retention times maintaining allowed for maintained effective drug concentrations against many clinically relevant pathogens for more than 48\u2003h for one formulation and more than 5\u2003days for the other. Both SDST formulations offer significant advantages over standard immediate\u2010release therapy in achieving PK\u2013PD goals and enhancing adherence. 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