Pharmacokinetic differentiation and consequences for normal microflora.

The pharmacokinetic properties of a drug are decisive for effective antibacterial therapy, the ability of the drug to reach a site of infection, but they also contribute to whether concentrations become undesirably high in places where the antibiotics are not wanted but where they may interfere with the normal microflora. The microflora in the intestines is particularly important because of the sheer numbers of bacteria present there and the consequences of imbalance such as diarrhoea and selection of bacteria resistant against antibiotics. For these reasons, high intestinal absorption, as can be achieved by the ampicillin prodrugs, is important. This leads to high utilization of the dose and decisively reduces the frequency of loose stools and diarrhoea. Improvement of biopharmaceutical properties of oral dosage forms need combined pharmaceutical and pharmacokinetic assessment. High elimination in the bile can have a considerable impact on the intestinal microflora as, for instance, agents with broad spectrum, like beta-lactamase stable cephalosporins that are not absorbed but remain within the gastrointestinal tract. Cephalosporins have been implicated in the selection of beta-lactamase producing enterobacteria. Narrow spectrum has been a sales argument, but if these agents produce high intestinal concentrations, as is the case with formulations of erythromycin that have poor formulations and are incompletely absorbed, the result may be disturbed faecal flora. In addition to low absorption, erythromycin elimination by bile is high. Clostridium difficile may in particular be selected by high concentrations of antibacterial drugs in the intestines.(ABSTRACT TRUNCATED AT 250 WORDS)