Effect of beta-lactam prodrugs on human intestinal microflora.

The ampicillin prodrugs bacampicillin, pivampicillin, and talampicillin, the mecillinam prodrug pivmecillinam and the sulbactam prodrug sulbactam pivoxil all have a greatly improved oral availability compared to the parent drug. They show no antibacterial activity themselves until transformed into active drugs after absorption. This double advantage makes them less likely to influence the intestinal microbial ecosystem. Ampicillin has been reported to cause marked changes in the colon microflora, particularly as regards Enterobacter species, Klebsiella species, enterococci, lactobacilli, bacteroides, and clostridia, in contrast to pivampicillin, which did not exert much influence. Similarly, talampicillin has been reported to have less influence than ampicillin on the colon flora. Diarrhoea was more common after ampicillin and was accompanied by an overgrowth of Candida. Pivmecillinam has been reported to reduce the number of Escherichia coli and lactobacilli. No changes were seen in the colon flora of subjects receiving bacampicillin tablets. This was verified in a parallel group study, in which one group was given the combination of bacampicillin and sulbactam pivoxil, the other bacampicillin, for seven days. Of the subjects given the combination, five had a moderate and ten a considerable change in their colon microflora. The subjects were often heavily colonized by new aerobic strains such as enterococci, E. coli, Bacillus, Enterobacter, Aeromonas, and yeasts. Among the anaerobes, Veillonella, the bifidobacteria-lactobacillus group, and bacteroides decreased. Some strains of clostridia decreased but there was also a colonization with new strains. One subject was colonized with Clostridium difficile. Diarrhoea was seen only during the week of active drug administration in the group given the combination. The symptoms generally appeared on the second or third day of treatment and had, in most cases, subsided at the end of treatment. The results illustrate the correlation between disturbances in the intestinal microbial ecosystem and intestinal adverse reactions.