Wrestling with Recurrent Infections

10,11 Furthermore, fidaxomicin has a narrower spectrum of activity than vancomycin and metronidazole, meaning it is less likely to disturb the gut bacteria which normally help prevent invaders such as C. difficile from flourishing. Indeed, fidaxomicin has been shown to have a much muted effect on host flora. The drug, which last month received a unanimous recommendation for approval by an FDA advisory committee, was under review at the US agency and the European Medicines Agency when this article went to press. (Disclosure: Glenn S. Tillotson currently works for Optimer Pharmaceuticals, Inc.)

Other antimicrobial products in the queue include ramoplanin, an antibiotic that blocks bacterial cell wall synthesis, which is being developed by Florida–based Nanotherapeutics and is slated to begin Phase III trials later this year; and Massachusetts–based Cubist Pharmaceuticals’ drug CB-183,315, which disrupts the bacterial cell membrane function and is currently in Phase II clinical testing.

Another potential therapy for CDI takes a step outside the box of traditional medicine. Known as fecal bacteriotherapy, or fecal transplants, it involves the creation of a saline-diluted solution of fecal matter from a healthy donor, which is introduced into a CDI patient’s gastrointestinal tract using a catheter or enema. Based on reestablishing a normal, healthy gut flora, whose disturbance often allows the flourishing of C. difficile, the treatment has been used sporadically in North America for the last few decades. Recently, however, it has begun to gain acceptance among clinicians and patients, and a 2009 review of 100 Scandinavian cases reported an 89 percent cure rate among CDI patients.¹² Last October, epidemiologist Susy Hota of Toronto General Hospital began recruiting patients for the first North American randomized, controlled trial of the procedure, in combination with a 2-week regimen of oral vancomycin.

While these drugs and therapies hold promise as treatments for killing the bacteria after infection takes hold, other approaches are being developed to help protect at-risk patients before infection even begins. It is often flaws or weaknesses in the host’s immune system that enable C. difficile to become established more easily in the gut. As people age, their ability to make sufficient or appropriate antibodies goes down, which allows pathogens such as C. difficile to more easily evade the immune response. As the average age of CDI patients is more than 65 years, approaches that bolster immune function are being investigated to help quell the escalation in CDI.

Until recently, researchers did not know how to build a vaccine that would effectively target C. difficile. Rather than target the bacterium itself, researchers recognized that the body’s ability to protect against toxins A and B was of paramount importance in the fight, although the production of antibodies that block the adherence of C. difficile to the colon wall in the first place would be even better. There are now at least three approaches that aim to arm the immune system to fight CDI at various stages of the infection.

One such therapy is a vaccine being developed by Sanofi-Pasteur that uses neutralized forms of toxins A and B to bolster patients’ ability to make immunoglobulins that bind to and eliminate the disease-causing toxins. Phase I studies have shown that this vaccine, composed of a proprietary ratio of the modified toxins, was well tolerated and resulted in increased production of antibodies specific to the two toxins in healthy participants; however, the response rate was lower in those over 70 years old compared with those aged 25 years. The vaccine is currently being tested for the prevention of CDI recurrence in a Phase II trial in the United Kingdom and the United States. Last November, shortly after the FDA granted the vaccine a fast-track designation to expedite its development, the vaccine maker announced the initiation of a second Phase II trial—this one for primary prevention of CDI in at-risk individuals in the United States.

Merck & Co. also has a potential CDI treatment in its pipeline—a monoclonal antibody called MK-3415A that similarly targets toxins A and B. Last year, the pharmaceutical company reported that recurrence rates dropped by up to 72 percent in a Phase II trial of patients also taking metronidazole or vancomycin.¹³ Based on those results, Merck had planned to follow up with Phase III studies “in the near term,” according to a company spokesperson, but has currently put the program on hold “in view of ongoing interactions with regulatory authorities.”

A third alternative approach to managing CDI is to prevent the pathogenic strain of C. difficile from colonizing the bowel in the first place—a strategy that should subsequently thwart the production of toxins and spores. Previous studies in hamsters showed that infection with strains of C. difficile that do not produce the two toxins, but in all other ways resemble the pathogenic C. difficile, can protect against further infection. Because these harmless bacteria presumably attach to the same bowel sites as the dangerous bacteria, they block all points of contact for the virulent variety. ViroPharma Incorporated has partnered with Dr. Dale Gerding, an infectious disease physician at Hines VA Hospital in Chicago, to evaluate this biotherapeutic approach. Phase I data suggest that this nontoxigenic C. difficile strain is well tolerated and colonizes the bowel of healthy volunteers, and the company plans to begin a Phase II trial this year. (Disclosure: Glenn S. Tillotson used to work for ViroPharma Incorporated.)

Few other infections have been the subject of so many varied therapeutic approaches. Those currently in development for the treatment of CDI will no doubt be key to beating the newly emerging superstrains of C. difficile. In addition, the use of new patient assessments that assist in selecting the right therapy for the right patient is of paramount importance for reducing disease recurrence.

Currently, doctors treat CDI patients on the basis of disease severity at the time the patient is seen, as per clinical guidelines, and prescribe either vancomycin or metronidazole, depending on the early signs and symptoms. But immediate clinical outcome is not always indicative of the long-term consequences of recurrent infections. Recent studies suggest that there may be clinical and historical risk factors that are related to a higher incidence of recurrence, including age, prior CDI, concomitant antibiotics, renal failure, and immunocompromised status. Elderly patients, for example, are more likely to have had recent antibiotics for unrelated infections, which can decrease host defenses and perturb the normal gut flora, reducing populations of C. difficile’s inhibitors and competitors in the gastrointestinal tract. Other age-related diseases, such as cancer, can also adversely affect host defenses, thus reducing the patient’s ability to fight off invaders, and often require therapies that disrupt the gut flora. Prior infection by C. difficile may also lead to an increased risk of recurrence because of residual spores left behind in the bowel, where they await the right environment for regermination. It is the recurrence of CDI that presents a significant burden to health care systems and patients. An 8-year-old estimate assesses the annual excess hospital costs in the United States at $3.2 billion,¹⁴ and the costs now could be as high as $9.55 billion annually.

Almost a century ago Paul Ehrlich, the grandfather of chemotherapy, presciently warned of the emergence of organisms which would thwart our best medical efforts by developing means of resistance unless we “frapper fort et frapper vite,” roughly translated as “hit hard and hit fast.” When dealing with CDI, we must embrace this edict by choosing the right weapon for the right patient at the right time. Otherwise, Ehrlich’s predictions will continue to come true.

Glenn S. Tillotson used to work for ViroPharma Incorporated and now works for Optimer Pharmaceuticals, Inc., in San Diego, Calif. Gayatri Vedantam is an assistant professor in the Department of Veterinary Science and Microbiology at the University of Arizona in Tucson, as well as a research health scientist in the Southern Arizona VA Healthcare System. The authors wish to thank Joni Tillotson, a biology undergraduate student at Immaculata University, for her manuscript research and database compilation.

This article is adapted from a review in F1000 Biology Reports. DOI: 10.3410/M3-6 (open access at http://bit.ly/CdiffTher). For citation purposes, please refer to that version.