Guarding the gut

Broad-spectrum -lactam antibiotics, such as ampicillin, can disrupt the ecology of the gut microflora, resulting in diarrhea and other side effects. In the worst-case scenario, individuals with weakened immune systems can go on to develop antibiotic-induced pseudomembranous colitis, a condition caused by overgrowth of the gut anaerobe Clostridium difficile. Disrupting the gut and intestinal flora also can enable antibiotic-resistant bacteria to colonize the region because of dwindling numbers of normal inhabitants that keep foreign invaders at bay. The presence of these organisms puts patients at greater risk of “superinfections” caused by organisms such as vancomycin-resistant enterococci (VRE), which can be difficult or impossible to treat.

To tackle this problem, scientists at Ipsat Therapies, Ltd. (Espoo, Finland), and the University of Helsinki (Helsinki, Finland) have developed a novel therapeutic concept called targeted recombinant -lactamase. Their unusual approach uses -lactamase, an enzyme produced by bacteria to degrade -lactam antibiotics. During antibiotic therapy, the enzyme is delivered to the small bowel via a pH-dependent, controlled-release formulation that enables targeted antibiotic degradation in this region, thereby preserving the normal flora. The scientists presented their findings at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago in December.

In animals receiving both ampicillin and the enzyme, the antibiotic was barely detectable in the intestine, while it was still present at therapeutic levels in the serum. Significantly, no -lactamase enzyme could be detected in the serum. As intended, targeted enzymatic degradation of the antibiotic prevented disturbances among the bacterial strains found in the intestine.

Phase I clinical trials in Finland and the United States are set to begin to assess safety among participants receiving ampicillin, says pharmacologist Kai Lindevall, president and CEO of Ipsat Therapies.

Preventing antibiotic-resistant bugs from taking up residence is one means of decreasing their incidence and the infections they cause. “Many antibiotics have an impact on anaerobes in the colon that facilitates colonization of VRE,” says Lindevall. The company’s next goal, he says, is to see if the enzyme can prevent this from happening. In the meantime, a similar product is in the works to prevent the disruption of gut microflora stemming from the use of other types of antibiotics.