Implications on emergence of antimicrobial resistance as a critical aspect in the design of oral sustained release delivery systems of antimicrobials.
OBJECTIVE
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.
Hoffman
Amnon
A
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem, 91120, Israel. ahoffman@cc.huji.ac.il
Horwitz
Ehud
E
Hess
Shmuel
S
Cohen-Poradosu
Ronit
R
Kleinberg
Lilach
L
Edelberg
Anna
A
Shapiro
Mervyn
M
D000284:Administration, Oral; D000658:Amoxicillin / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D003106:Colon / Q000187:drug effects / Q000382:microbiology; D015169:Colony Count, Microbial; D003692:Delayed-Action Preparations; D004339:Drug Compounding; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D005243:Feces / Q000382:microbiology; D005772:Gastrointestinal Transit; D007082:Ileum / Q000187:drug effects / Q000382:microbiology; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000382:microbiology; D007441:Intubation, Gastrointestinal; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D001618:beta-Lactamases / Q000008:administration & dosage* / Q000378:metabolism
D000890:Anti-Infective Agents; D003692:Delayed-Action Preparations; D000658:Amoxicillin; D001618:beta-Lactamases