Scanning electron micrograph of Clostridium difficile

New antimicrobials, the increased pathogenicity and emergence of hyper-toxin-producing strains of Clostridium difficile, and new ways to treat recurrent genital herpes were some of the issues addressed at the recent 45th annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held recently in Washington, D.C.

Future therapies may spare the anaerobic flora, the disruption of which by current antibiotic therapy is responsible for the high rates of relapse observed in C. difficile-associated diarrhea.

"Intuitively, clinicians have become aware that new treatments need to be more selective in killing or neutralizing the pathogen, yet allowing the normal microbiota to rebalance itself," said Thomas J. Louie, M.D., director of infection control at the University of Calgary, Alberta.

Metronidazole with vancomycin as a backup have been the two most commonly used specific therapies to treat C. difficile-associated diarrhea, although vancomycin is the only drug approved for this indication. Up to 90% of patients respond to these therapies, but diarrhea recurs in about 20% of patients. Furthermore, fulminant disease has resulted in colectomies, clinical sepsis, and death.

Suppression of the anaerobic flora is responsible for relapsing cases, which can last months or years. With vancomycin, high concentrations in the fecal biomass are thought to contribute to suppression of normal flora, accounting for relapsing disease, said Louie.

Louie's group has investigated two novel therapies that may overcome the problems with current antibiotic therapy. One is tolevamer (Genzyme), a nonabsorbed polystyrene binder/neutralizer of the C. difficile cytotoxins A and B. By binding the toxins produced by C. difficile but ignoring the organism itself, "you take the bullets out of the gun," he said.

A large, phase II trial of 287 patients compared tolevamer given for 14 days with vancomycin, 125 mg/ day for 10 days. Clinical response to the 6-gm daily dose of tolevamer was non-inferior to the response obtained with vancomycin. There were too few patients in the trial to determine whether tolevamer was associated with a lower rate of relapsing disease.

The macrocyclic antibiotic PAR 101 (PAR Pharmaceuticals) also shows promise in the treatment of C. difficile-associated diarrhea. This agent has activity against C. difficile that is eight-to 10-fold greater than that of vancomycin. In addition, activity against most members of the normal intestinal flora is limited. In dose-ranging studies, a full course of PAR-101 resulted in responses in 41 of 45 patients, with only two relapses, both approximately one month after therapy. Complete relief of symptoms was achieved by 87% of patients receiving 400 mg/day.

"While the precise role of each of these new modalities for the treatment of C. difficile-associated diarrhea is to be determined, it is anticipated that both metronidazole and vancomycin could be superseded by treatments that have comparable or higher response rates, lesser relapse by virtue of greater selectivity for C. difficile by allowing the normal flora to return, and lesser selection of antibiotic-resistant nosocomial pathogens," Louie said.

In other news, single-day, high-dose oral famciclovir (Famvir, Novartis) treatment shortens the duration of recurrent genital herpes. In a study of 329 patients by Fred Aoki, M.D., 1,000 mg of famciclovir taken twice for one day significantly reduced the time to healing of genital herpes lesions compared with placebo.

Famciclovir also doubled the likelihood that vesicular lesions would not develop during a genital herpes recurrence, said Aoki, professor of medicine and pharmacology and therapeutics, University of Manitoba, Winnipeg, Canada. "Single-day famciclovir, started within six hours of onset of genital herpes outbreak, is effective, well tolerated, and convenient, with the potential for improving the overall management of herpes," he said.

Tigecycline (Tygacil, Wyeth) has demonstrated high levels of in vitro activity against a variety of resistant pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and extended-spectrum beta-lactamase-producing Enterobacteriaceae, reported Jack Johnson, president, International Health Management Associates Inc., Schaumburg, Ill.