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 β-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 β-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 β-lactam prior to entering the colon, by infusion of a β-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.
Bibliographical noteFunding Information:
This study was supported in part by the David R. Bloom Center for Pharmacy at the Hebrew University. A. Hoffman is affiliated with this center.
- Antimicrobial resistance
- Colonic microflora
- Delayed action preparations
- Oral dosage form
- β-lactam antibiotic