Hospital-acquired infections (HAIs) afflict as many as 5% of hospital patients, particularly those receiving antibiotic therapy. The antibiotics are thought to damage normal gut microflora, allowing pathogens to flourish. Clostridium difficile is one of the most common pathogens, causing diarrhea, intestinal inflammation (colitis) and even death in infected patients. Management of C. difficile incurs an estimated $3.5 billion in health care costs in the US annually, and costs are expect to increase with the emergence of new, more virulent strains of C. difficile.

C. difficile is resistant to many antibiotics and is normally treated with one of two potent antibiotics (metronidazole or vancomycin). Such treatment carries two key drawbacks: relapses are common, and the treatment may contribute to increasing antibiotic resistance among bacteria. Effective alternatives to antibiotics are greatly needed. To address this need, recent research has explored a new treatment strategy for C. difficile that relies on the body's own defenses against infection. The results may lead to development of new approaches for treating C. difficile infection as well as other bacterial diseases.

The new research first examined the process by which C. difficile causes disease. C. difficile releases toxins into the gut that must be cleaved in order to enter gut epithelial cells. Cleavage is carried out by a cysteine protease that requires the presence of a cofactor, inositol hexakisphosphate (InsP6). After cleavage, the toxins can enter the gut epithelium, where they trigger inflammation. But they also trigger the host system to release chemicals that effectively neutralize C. difficile's 'cleaver' cysteine protease, preventing further toxin entry (Nat. Med. doi:10.1038/nm.2405; published online 21 August 2011).

Tor Savidge (University of Texas Medical Branch, Galveston) and colleagues found a way to induce this toxin neutralization process, called S-nitrosylation, using S-nitrosoglutathione (GSNO) in mice infected with C. difficile. Infected mice treated with GSNO became less ill and were more likely to survive infection than were untreated mice. The survival rate at 4 days after C. difficile infection was 85% in mice given GSNO plus the cofactor InsP6 compared with 25% in untreated mice. The GSNO treatment was less effective than conventional treatment with vancomycin, however, which had a 100% survival rate at 4 days after infection.

“Our study suggests a novel therapeutic approach for treating Clostridium difficile infection by exploiting a newly discovered defense mechanism that has evolved in humans to inactivate microbial toxins,” Savidge said in a press release.