Implications on emergence of antimicrobial resistance as a critical aspect in the design of oral sustained release delivery systems of antimicrobials

Abstract

Purpose: To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used.

Methods: Effects of an orally administered model beta-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a beta-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials.

Results: Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the beta-lactam prior to entering the colon, by infusion of a beta-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria.

Conclusions: This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.